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TGFβ4 alleviates the phenotype of Charcot-Marie-Tooth disease type 1A

SUMMARY:
CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGFβ4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.

TITLE:
TGFβ4 alleviates the phenotype of Charcot-Marie-Tooth disease type 1A

DESCRIPTION:
The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGFβ4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells (SCs), which might be one of…

CONTENT:
Brain. 2023 May 5:awad147. doi: 10.1093/brain/awad147. Online ahead of print.

ABSTRACT

The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGFβ4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells (SCs), which might be one of the downstream effector in CMT1A. Administration of Nodal protein at the developmental stage of peripheral nerves induced the demyelinating phenotype in vivo. Second, we further isolated TGFβ4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGFβ4-fragment crystallizable (Fc) fusion protein, CX201, and demonstrated that its application had promyelinating efficacy in SCs. CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGFβ4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.

PMID:37143322 | DOI:10.1093/brain/awad147

SOURCE:
Brain : a journal of neurology

TAGS:
CX201

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-05-05T05:15:23Z

DATE – DOI: 2023-05-05T05:15:23Z
DATE – PUBMED: 2023 May 5
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 05 May 2023 06:00:00 -0400

DATE – RETRIEVED:
05/05/23 06:38AM
2023-05-05T06:38:22-04:00

FEATURED IMAGE:
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IDENTIFIER:
pmid:37143322,doi:10.1093/brain/awad147

PUBMED ID:
pubmed:37143322

DOI:
10.1093/brain/awad147

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37143322/

LINK – DOI:
https://doi.org/10.1093/brain/awad147

LINK – PUBLISHER:
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad147/7152691

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-05-05T06:38:22-04:00, https://www.cmttreatmentreport.com.

Charcot-Marie-Tooth neuropathies: current gene therapy advances and the route towards translation

SUMMARY:
This article is protected by copyright. All rights reserved.

TITLE:
Charcot-Marie-Tooth neuropathies: current gene therapy advances and the route towards translation

DESCRIPTION:
Charcot-Marie-Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unravelling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification and editing of genetic…

CONTENT:
J Peripher Nerv Syst. 2023 Mar 25. doi: 10.1111/jns.12543. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unravelling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification and editing of genetic material. For most CMT neuropathies gene- and disease- and even mutation- specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular-genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non-human-primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale-up potential and safety. The path towards clinical trials is faced with further challenges, but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies. This article is protected by copyright. All rights reserved.

PMID:36965137 | DOI:10.1111/jns.12543

SOURCE:
Journal of the peripheral nervous system : JPNS

TAGS:
This article is protected by copyright All rights reserved This article is protected by copyright All rights reserved

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-03-25T19:55:44Z

DATE – DOI: 2023-03-25T19:55:44Z
DATE – PUBMED: 2023 Mar 25
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 25 Mar 2023 06:00:00 -0400

DATE – RETRIEVED:
03/25/23 06:59PM
2023-03-25T18:59:21-04:00

FEATURED IMAGE:
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IDENTIFIER:
pmid:36965137,doi:10.1111/jns.12543

PUBMED ID:
pubmed:36965137

DOI:
10.1111/jns.12543

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36965137/

LINK – DOI:
https://doi.org/10.1111/jns.12543

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1111/jns.12543

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-03-25T18:59:21-04:00, https://www.cmttreatmentreport.com.

MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A

SUMMARY:
Mitochondria regulate acetylation of alpha-tubulin.

TITLE:
MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A

DESCRIPTION:
Acetylated microtubules play key roles in the regulation of mitochondria dynamics. It has however remained unknown if the machinery controlling mitochondria dynamics functionally interacts with the alpha-tubulin acetylation cycle. Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion, transport and tethering with the endoplasmic reticulum. The role of MFN2 in regulating…

CONTENT:
bioRxiv. 2023 Mar 16:2023.03.15.532838. doi: 10.1101/2023.03.15.532838. Preprint.

ABSTRACT

Acetylated microtubules play key roles in the regulation of mitochondria dynamics. It has however remained unknown if the machinery controlling mitochondria dynamics functionally interacts with the alpha-tubulin acetylation cycle. Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion, transport and tethering with the endoplasmic reticulum. The role of MFN2 in regulating mitochondrial transport has however remained elusive. Here we show that mitochondrial contacts with microtubules are sites of alpha-tubulin acetylation, which occurs through the MFN2-mediated recruitment of alpha-tubulin acetyltransferase 1 (ATAT1). We discover that this activity is critical for MFN2-dependent regulation of mitochondria transport, and that axonal degeneration caused by CMT2A MFN2 associated mutations, R94W and T105M, may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in regulating acetylated alpha-tubulin and suggest that disruption of the tubulin acetylation cycle play a pathogenic role in the onset of MFN2-dependent CMT2A.

PMID:36993604 | PMC:PMC10055074 | DOI:10.1101/2023.03.15.532838

SOURCE:
bioRxiv : the preprint server for biology

TAGS:
Mitochondria

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-03-17T05:20:33Z

DATE – DOI: 2023-03-17T05:20:33Z
DATE – PUBMED: 2023 Mar 16
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 30 Mar 2023 06:00:00 -0400

DATE – RETRIEVED:
03/30/23 07:08AM
2023-03-30T07:08:16-04:00

FEATURED IMAGE:
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IDENTIFIER:
pmid:36993604,pmc:PMC10055074,doi:10.1101/2023.03.15.532838

PUBMED ID:
pubmed:36993604

DOI:
10.1101/2023.03.15.532838

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36993604/

LINK – DOI:
https://doi.org/10.1101/2023.03.15.532838

LINK – PUBLISHER:
http://biorxiv.org/lookup/doi/10.1101/2023.03.15.532838

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-03-30T07:08:16-04:00, https://www.cmttreatmentreport.com.

Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

SUMMARY:
BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

TITLE:
Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

DESCRIPTION:
Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital…

CONTENT:
JCI Insight. 2023 Mar 16:e157191. doi: 10.1172/jci.insight.157191. Online ahead of print.

ABSTRACT

Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

PMID:36928301 | DOI:10.1172/jci.insight.157191

SOURCE:
JCI insight

TAGS:
BDNF

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-03-16T16:00:44Z

DATE – DOI: 2023-03-16T16:00:44Z
DATE – PUBMED: 2023 Mar 16
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 17 Mar 2023 06:00:00 -0400

DATE – RETRIEVED:
03/17/23 01:02PM
2023-03-17T13:02:52-04:00

FEATURED IMAGE:
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IDENTIFIER:
pmid:36928301,doi:10.1172/jci.insight.157191

PUBMED ID:
pubmed:36928301

DOI:
10.1172/jci.insight.157191

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36928301/

LINK – DOI:
https://doi.org/10.1172/jci.insight.157191

LINK – PUBLISHER:
http://insight.jci.org/articles/view/157191

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-03-17T13:02:52-04:00, https://www.cmttreatmentreport.com.

Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A

SUMMARY:
This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.

TITLE:
Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A

DESCRIPTION:
OBJECTIVES: Transcript sequencing of patient derived samples has been shown to improve the diagnostic yield for solving cases of likely Mendelian disorders, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.

CONTENT:
bioRxiv. 2023 Feb 7:2023.02.07.526487. doi: 10.1101/2023.02.07.526487. Preprint.

ABSTRACT

OBJECTIVES: Transcript sequencing of patient derived samples has been shown to improve the diagnostic yield for solving cases of likely Mendelian disorders, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.

METHODS: We applied short-read and full-length isoform cDNA sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.

RESULTS: We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts a branch point critical for intron 6 spicing. Full-length long-read isoform cDNA sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates five distinct altered splicing transcripts. All five altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 protein levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A).

DISCUSSION: This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.

PMID:36798371 | PMC:PMC9934537 | DOI:10.1101/2023.02.07.526487

SOURCE:
bioRxiv : the preprint server for biology

TAGS:
CMT2A

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-02-08T05:15:20Z

DATE – DOI: 2023-02-08T05:15:20Z
DATE – PUBMED: 2023 Feb 7
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 17 Feb 2023 06:00:00 -0500

DATE – RETRIEVED:
02/17/23 07:07AM
2023-02-17T07:07:14-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36798371,pmc:PMC9934537,doi:10.1101/2023.02.07.526487

PUBMED ID:
pubmed:36798371

DOI:
10.1101/2023.02.07.526487

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36798371/

LINK – DOI:
https://doi.org/10.1101/2023.02.07.526487

LINK – PUBLISHER:
http://biorxiv.org/lookup/doi/10.1101/2023.02.07.526487

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-02-17T07:07:14-05:00, https://www.cmttreatmentreport.com.

Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells harbouring MFN2 (mitofusin 2) mutation

SUMMARY:
mTORC2 is a novel molecular target that lies upstream of AKT to restore the cell proliferation rate in CMT2A fibroblasts.

TITLE:
Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells harbouring MFN2 (mitofusin 2) mutation

DESCRIPTION:
CONCLUSIONS: Overall, our study provides evidence for mTORC2, as a novel molecular target that lies upstream of AKT to restore the cell proliferation rate in CMT2A fibroblasts.

CONTENT:
Acta Myol. 2022 Dec 31;41(4):201-206. doi: 10.36185/2532-1900-085. eCollection 2022.

ABSTRACT

OBJECTIVE: Mitofusin 2 (MFN2) is a mitochondrial outer membrane protein that serves primarily as a mitochondrial fusion protein but has additional functions including the tethering of mitochondrial-endoplasmic reticulum membranes, movement of mitochondria along axons, and control of the quality of mitochondria. Intriguingly, MFN2 has been referred to play a role in regulating cell proliferation in several cell types such that it acts as a tumour suppressor role in some forms of cancer. Previously, we found that fibroblasts derived from a Charcot-Marie-Tooth disease type 2A (CMT2A) patient with a mutation in the GTPase domain of MFN2 exhibit increased proliferation and decreased autophagy.

METHODS: Primary fibroblasts from a young patient affected by CMT2A harbouring c.650G > T/p.Cys217Phe mutation in the MFN2 gene were evaluated versus a healthy control to measure the proliferation rate by growth curves analysis and to assess the phosphorylation of protein kinase B (AKT) at Ser473 in response to different doses of torin1, a selective catalytic ATP-competitive mammalian target of rapamycin complex (mTOR) inhibitor, by immunoblot analysis.

RESULTS: Herein, we demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) is highly activated in the CMT2AMFN2 fibroblasts to promote cell growth via the AKT(Ser473) phosphorylation-mediated signalling. We report that torin1 restores CMT2AMFN2 fibroblasts’ growth rate in a dose-dependent manner by decreasing AKT(Ser473) phosphorylation.

CONCLUSIONS: Overall, our study provides evidence for mTORC2, as a novel molecular target that lies upstream of AKT to restore the cell proliferation rate in CMT2A fibroblasts.

PMID:36793649 | PMC:PMC9896598 | DOI:10.36185/2532-1900-085

SOURCE:
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology

TAGS:
mTORC2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-02-03T11:21:47Z

DATE – DOI: 2023-02-03T11:21:47Z
DATE – PUBMED: 2022 Dec 31
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 16 Feb 2023 06:00:00 -0500

DATE – RETRIEVED:
02/16/23 07:07AM
2023-02-16T07:07:12-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36793649,pmc:PMC9896598,doi:10.36185/2532-1900-085

PUBMED ID:
pubmed:36793649

DOI:
10.36185/2532-1900-085

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36793649/

LINK – DOI:
https://doi.org/10.36185/2532-1900-085

LINK – PUBLISHER:

Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells harbouring MFN2 (mitofusin 2) mutation

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-02-16T07:07:12-05:00, https://www.cmttreatmentreport.com.

Novel Variants in MPV17, PRX, GJB1 , and SACS Cause Charcot-Marie-Tooth and Spastic Ataxia of Charlevoix-Saguenay Type Diseases

SUMMARY:
Whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot-Marie-Tooth disease (CMT) and spastic ataxia of Charlevoix-Saguenay type.

TITLE:
Novel Variants in MPV17, PRX, GJB1 , and SACS Cause Charcot-Marie-Tooth and Spastic Ataxia of Charlevoix-Saguenay Type Diseases

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix-Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS…

CONTENT:
Genes (Basel). 2023 Jan 27;14(2):328. doi: 10.3390/genes14020328.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix-Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS . In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS , was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX , which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17 , SACS , PRX , and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot-Marie-Tooth disease (CMT) and spastic ataxia of Charlevoix-Saguenay type.

PMID:36833258 | DOI:10.3390/genes14020328

SOURCE:
Genes

TAGS:
Whole exome sequencing

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-01-30T11:43:26Z

DATE – DOI: 2023-01-30T11:43:26Z
DATE – PUBMED: 2023 Jan 27
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 25 Feb 2023 06:00:00 -0500

DATE – RETRIEVED:
02/25/23 11:05AM
2023-02-25T11:05:14-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36833258,doi:10.3390/genes14020328

PUBMED ID:
pubmed:36833258

DOI:
10.3390/genes14020328

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36833258/

LINK – DOI:
https://doi.org/10.3390/genes14020328

LINK – PUBLISHER:
https://www.mdpi.com/2073-4425/14/2/328

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-02-25T11:05:14-05:00, https://www.cmttreatmentreport.com.

Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease

SUMMARY:
cemdomespib therapy improved CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.

TITLE:
Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease

DESCRIPTION:
Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests…

CONTENT:
ACS Pharmacol Transl Sci. 2023 Jan 20;6(2):306-319. doi: 10.1021/acsptsci.2c00223. eCollection 2023 Feb 10.

ABSTRACT

Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.

PMID:36798471 | PMC:PMC9926526 | DOI:10.1021/acsptsci.2c00223

SOURCE:
ACS pharmacology & translational science

TAGS:
cemdomespib

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-01-20T13:19:21Z

DATE – DOI: 2023-01-20T13:19:21Z
DATE – PUBMED: 2023 Jan 20
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 17 Feb 2023 06:00:00 -0500

DATE – RETRIEVED:
02/17/23 07:07AM
2023-02-17T07:07:05-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36798471,pmc:PMC9926526,doi:10.1021/acsptsci.2c00223

PUBMED ID:
pubmed:36798471

DOI:
10.1021/acsptsci.2c00223

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36798471/

LINK – DOI:
https://doi.org/10.1021/acsptsci.2c00223

LINK – PUBLISHER:
https://pubs.acs.org/doi/10.1021/acsptsci.2c00223

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-02-17T07:07:05-05:00, https://www.cmttreatmentreport.com.

Exercise induced myelin protein zero improvement in neuropathic pain rats

SUMMARY:
Swimming exercise improves myelin protein zero level in neuropathic rats along with attenuating neuropathic pain.

TITLE:
Exercise induced myelin protein zero improvement in neuropathic pain rats

DESCRIPTION:
CONCLUSIONS: Swimming exercise improves myelin protein zero level in neuropathic rats along with attenuating neuropathic pain. This is a promising approach in improving neuropathological disorders including Charcot-Marie-Tooth and Dejerine-Sottas disease.

CONTENT:
Somatosens Mot Res. 2023 Jan 11:1-6. doi: 10.1080/08990220.2022.2158800. Online ahead of print.

ABSTRACT

PURPOSE: Aerobic exercise including swimming plays a suitable role in improving somatosensory injuries. Neuropathic pain is a debilitating condition that occurs following injury or diseases of somatosensory system. In the present study, we tried to investigate the effect of exercise on myelin protein zero of sciatic nerve injured rats.

MATERIALS AND METHODS: Forty male rats (180-220 g) were divided into five groups (intact, sham, sham + exercise, neuropathy, and neuropathy + exercise). Right Sciatic nerve of anesthetized rats was exposed and loosely ligated (four ligations with 1 mm apart) using catgut chromic sutures to induce neuropathy. After 3 days of recovery, swimming exercise began (20 min/day/5 days a week/4 weeks). Mechanical allodynia and thermal hyperalgesia were detected using Von Frey filaments and plantar test, respectively. Sciatic nerve at the place of injury was dissected out to measure the myelin protein zero by western blot analysis. In the intact and sham groups, sciatic nerve removed at the place similar to injured group.

RESULTS: We found that neuropathy significantly (p < 0.05) reduced paw withdrawal mechanical and thermal thresholds and swimming exercise significantly (p < 0.05) increased paw withdrawal mechanical and thermal thresholds compared to the neuropathy group. Moreover, we found that MPZ level significantly (p < 0.01) decreased in neuropathy group against that in sham group, and exercise prominently (p < 0.05) reversed MPZ level towards control level. CONCLUSIONS: Swimming exercise improves myelin protein zero level in neuropathic rats along with attenuating neuropathic pain. This is a promising approach in improving neuropathological disorders including Charcot-Marie-Tooth and Dejerine-Sottas disease. PMID:36630644 | DOI:10.1080/08990220.2022.2158800 SOURCE: Somatosensory & motor research TAGS: swimming CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2023-01-11T20:18:43Z DATE - DOI: 2023-01-11T20:18:43Z DATE - PUBMED: 2023 Jan 11 DATE OUTPUT MATCHED: True DATE - ADDED: Wed, 11 Jan 2023 06:00:00 -0500 DATE - RETRIEVED: 01/11/23 07:04PM 2023-01-11T19:04:57-05:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:36630644,doi:10.1080/08990220.2022.2158800 PUBMED ID: pubmed:36630644 DOI: 10.1080/08990220.2022.2158800 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/36630644/ LINK - DOI: https://doi.org/10.1080/08990220.2022.2158800 LINK - PUBLISHER: https://www.tandfonline.com/doi/full/10.1080/08990220.2022.2158800 REFERENCES: CMT Treatment Report, Urgent Research, 2023-01-11T19:04:57-05:00, https://www.cmttreatmentreport.com.

A meta-analysis on the prevalence of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies

SUMMARY:
CMT&RIPNs are probably prevalent in older ages, males, and Northern Europe.

TITLE:
A meta-analysis on the prevalence of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies

DESCRIPTION:
CONCLUSION: CMT&RIPNs are relatively more prevalent as CMT1 in the disease subtypes, and probably prevalent in older ages, males, and Northern Europe. More studies on the epidemiological characteristics of CMT&RIPNs with well-defined diagnosis criteria are needed to improve the prevalence evaluation and to arouse more attention to health care support.

CONTENT:
J Neurol. 2023 Jan 11. doi: 10.1007/s00415-023-11559-8. Online ahead of print.

ABSTRACT

BACKGROUND: Charcot-Marie-Tooth disease and related inherited peripheral neuropathies (CMT&RIPNs) brings great suffering and heavy burden to patients, but its global prevalence rates have not been well described.

METHODS: We searched major English and Chinese databases for studies reporting the prevalence of CMT&RIPNs from the establishment of the databases to September 26, 2022. Based on the age, gender, study design, study region, and disease subtype, the included studies were correspondingly synthesized for meta-analyses on the overall prevalence and/or the subgroup analyses by using pool arcsine transformed proportions in the random-effects model.

RESULTS: Of the finally included 31 studies, 21 studied the whole age population and various types of CMT&RIPNs, and the others reported specific disease subtype(s) or adult or non-adult populations. The pooled prevalence was 17.69/100,000 (95% CI 12.32-24.33) for the whole age population and significantly higher for CMT1 [10.61/100,000 (95% CI 7.06-14.64)] than for other subtypes (P’ < 0.001). Without statistical significance, the prevalence seemed higher in those aged ≥ 16 or 18 years (21.02/100,000) than in those aged < 16 years (16.13/100,000), in males (22.50/100,000) than in females (17.95/100,000), and in Northern Europe (30.97/100,000) than in other regions. CONCLUSION: CMT&RIPNs are relatively more prevalent as CMT1 in the disease subtypes, and probably prevalent in older ages, males, and Northern Europe. More studies on the epidemiological characteristics of CMT&RIPNs with well-defined diagnosis criteria are needed to improve the prevalence evaluation and to arouse more attention to health care support. PMID:36631678 | DOI:10.1007/s00415-023-11559-8 SOURCE: Journal of neurology TAGS: CMTRIPNs CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2023-01-11T17:09:25Z DATE - DOI: 2023-01-11T17:09:25Z DATE - PUBMED: 2023 Jan 11 DATE OUTPUT MATCHED: True DATE - ADDED: Wed, 11 Jan 2023 06:00:00 -0500 DATE - RETRIEVED: 01/12/23 01:03AM 2023-01-12T01:03:04-05:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:36631678,doi:10.1007/s00415-023-11559-8 PUBMED ID: pubmed:36631678 DOI: 10.1007/s00415-023-11559-8 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/36631678/ LINK - DOI: https://doi.org/10.1007/s00415-023-11559-8 LINK - PUBLISHER: https://link.springer.com/10.1007/s00415-023-11559-8 REFERENCES: CMT Treatment Report, Urgent Research, 2023-01-12T01:03:04-05:00, https://www.cmttreatmentreport.com.

Electroceutical approach ameliorates intracellular PMP22 aggregation and promotes pro-myelinating pathways in a CMT1A in vitro model

SUMMARY:
This study demonstrates its effectiveness towards ameliorating biomolecular abnormalities in an in vitro model of CMT1A, an inherited peripheral neuropathy. These findings will facilitate the clinical translation of an electroceutical treatment for CMT1A.

TITLE:
Electroceutical approach ameliorates intracellular PMP22 aggregation and promotes pro-myelinating pathways in a CMT1A in vitro model

DESCRIPTION:
Charcot-Marie-Tooth disease subtype 1A (CMT1A) is one of the most prevalent demyelinating peripheral neuropathies worldwide, caused by duplication of the peripheral myelin protein 22 (PMP22) gene, which is expressed primarily in Schwann cells (SCs). PMP22 overexpression in SCs leads to intracellular aggregation of the protein, which eventually results in demyelination. Unfortunately, previous biochemical approaches have not resulted in an approved treatment for CMT1A disease, compelling the…

CONTENT:
Biosens Bioelectron. 2022 Dec 30;224:115055. doi: 10.1016/j.bios.2022.115055. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease subtype 1A (CMT1A) is one of the most prevalent demyelinating peripheral neuropathies worldwide, caused by duplication of the peripheral myelin protein 22 (PMP22) gene, which is expressed primarily in Schwann cells (SCs). PMP22 overexpression in SCs leads to intracellular aggregation of the protein, which eventually results in demyelination. Unfortunately, previous biochemical approaches have not resulted in an approved treatment for CMT1A disease, compelling the pursuit for a biophysical approach such as electrical stimulation (ES). However, the effects of ES on CMT1A SCs have remained unexplored. In this study, we established PMP22-overexpressed Schwannoma cells as a CMT1A in vitro model, and investigated the biomolecular changes upon applying ES via a custom-made high-throughput ES platform, screening for the condition that delivers optimal therapeutic effects. While PMP22-overexpressed Schwannoma exhibited intracellular PMP22 aggregation, ES at 20 Hz for 1 h improved this phenomenon, bringing PMP22 distribution closer to healthy condition. ES at this condition also enhanced the expression of the genes encoding myelin basic protein (MBP) and myelin-associated glycoprotein (MAG), which are essential for assembling myelin sheath. Furthermore, ES altered the gene expression for myelination-regulating transcription factors Krox-20, Oct-6, c-Jun and Sox10, inducing pro-myelinating effects in PMP22-overexpressed Schwannoma. While electroceuticals has previously been applied in the peripheral nervous system towards acquired peripheral neuropathies such as pain and nerve injury, this study demonstrates its effectiveness towards ameliorating biomolecular abnormalities in an in vitro model of CMT1A, an inherited peripheral neuropathy. These findings will facilitate the clinical translation of an electroceutical treatment for CMT1A.

PMID:36630746 | DOI:10.1016/j.bios.2022.115055

SOURCE:
Biosensors & bioelectronics

TAGS:
#CMT1A

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-12-31T00:40:31Z

DATE – DOI: 2022-12-31T00:40:31Z
DATE – PUBMED: 2022 Dec 30
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 11 Jan 2023 06:00:00 -0500

DATE – RETRIEVED:
01/12/23 01:03AM
2023-01-12T01:03:06-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36630746,doi:10.1016/j.bios.2022.115055

PUBMED ID:
pubmed:36630746

DOI:
10.1016/j.bios.2022.115055

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36630746/

LINK – DOI:
https://doi.org/10.1016/j.bios.2022.115055

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0956566322010958

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-01-12T01:03:06-05:00, https://www.cmttreatmentreport.com.

How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease

SUMMARY:
The T118M mutation with the occurrence of long and/or repeated episodes of carpal tunnel syndrome.

TITLE:
How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease

DESCRIPTION:
Data from gnomAD indicates that a missense mutation encoding the T118M variation in human peripheral myelin protein 22 (PMP22) is found in roughly 1 of every 75 genomes of western European lineage (1:120 in the overall human population). It is unusual among PMP22 variants that cause Charcot-Marie-Tooth disease (CMT) in that it is not 100%-penetrant. Here, we conducted cellular and biophysical studies to determine why T118M PMP22 predisposes humans to CMT, but with only incomplete penetrance. We…

CONTENT:
J Biol Chem. 2022 Dec 26:102839. doi: 10.1016/j.jbc.2022.102839. Online ahead of print.

ABSTRACT

Data from gnomAD indicates that a missense mutation encoding the T118M variation in human peripheral myelin protein 22 (PMP22) is found in roughly 1 of every 75 genomes of western European lineage (1:120 in the overall human population). It is unusual among PMP22 variants that cause Charcot-Marie-Tooth disease (CMT) in that it is not 100%-penetrant. Here, we conducted cellular and biophysical studies to determine why T118M PMP22 predisposes humans to CMT, but with only incomplete penetrance. We found that T118M PMP22 is prone to mistraffic, but differs even from the WT protein in that increased expression levels do not result in a reduction in trafficking efficiency. Moreover, the T118M mutant exhibits a reduced tendency to form large intracellular aggregates relative to other disease mutants and even WT PMP22. NMR spectroscopy revealed that the structure and dynamics of T118M PMP22 resembled those of WT. These results show that the main consequence of T118M PMP22 in WT/T118M heterozygous individuals is a reduction in surface-trafficked PMP22, unaccompanied by formation of toxic intracellular aggregates. This explains the incomplete disease penetrance and the mild peripheral neuropathy observed for WT/T118M CMT cases. We also analyzed BioVU, a large biobank linked to de-identified electronic medical records, and found a statistically robust association of the T118M mutation with the occurrence of long and/or repeated episodes of carpal tunnel syndrome. Collectively, our results both illuminate the cellular effects of the T118M PMP22 variation leading to CMT disease and indicate a second disorder for which it is a risk factor.

PMID:36581210 | DOI:10.1016/j.jbc.2022.102839

SOURCE:
The Journal of biological chemistry

TAGS:
T118M

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-12-26T15:51:23Z

DATE – DOI: 2022-12-26T15:51:23Z
DATE – PUBMED: 2022 Dec 26
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 29 Dec 2022 06:00:00 -0500

DATE – RETRIEVED:
12/30/22 12:58AM
2022-12-30T00:58:10-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36581210,doi:10.1016/j.jbc.2022.102839

PUBMED ID:
pubmed:36581210

DOI:
10.1016/j.jbc.2022.102839

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36581210/

LINK – DOI:
https://doi.org/10.1016/j.jbc.2022.102839

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0021925822012820

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-12-30T00:58:10-05:00, https://www.cmttreatmentreport.com.

CMT1A current gene therapy approaches and promising biomarkers

SUMMARY:
Tinnitus might negatively affect emotional wellbeing and cognitive capacities in older people.

TITLE:
CMT1A current gene therapy approaches and promising biomarkers

DESCRIPTION:
Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral nervous system. CMT type 1A (CMT1A) is the most frequent type and accounts for almost ~50% of all diagnosed CMT cases. CMT1A results from the duplication of the peripheral myelin protein 22 (PMP22) gene. Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein…

CONTENT:
Neural Regen Res. 2023 Jul;18(7):1434-1440. doi: 10.4103/1673-5374.361538.

ABSTRACT

Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral nervous system. CMT type 1A (CMT1A) is the most frequent type and accounts for almost ~50% of all diagnosed CMT cases. CMT1A results from the duplication of the peripheral myelin protein 22 (PMP22) gene. Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response. This leads to Schwann cell apoptosis, dys- and de- myelination and secondary axonal degeneration, ultimately causing neurological disabilities. During the last decades, several different gene therapies have been developed to treat CMT1A. Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22. The therapeutic goal is to achieve gene silencing, directly or indirectly, thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss. As promising treatments are rapidly emerging, treatment-responsive and clinically relevant biomarkers are becoming necessary. These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A.

PMID:36571339 | DOI:10.4103/1673-5374.361538

SOURCE:
Neural regeneration research

TAGS:
Tinnitus

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-12-22T13:09:17Z

DATE – DOI: 2022-12-22T13:09:17Z
DATE – PUBMED:
DATE OUTPUT MATCHED: False

DATE – ADDED:
Mon, 26 Dec 2022 06:00:00 -0500

DATE – RETRIEVED:
12/26/22 12:57PM
2022-12-26T12:57:51-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36571339,doi:10.4103/1673-5374.361538

PUBMED ID:
pubmed:36571339

DOI:
10.4103/1673-5374.361538

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36571339/

LINK – DOI:
https://doi.org/10.4103/1673-5374.361538

LINK – PUBLISHER:
https://journals.lww.com/10.4103/1673-5374.361538

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-12-26T12:57:51-05:00, https://www.cmttreatmentreport.com.

Charcot-Marie-Tooth-1A and sciatic nerve crush rat models: insights from proteomics

SUMMARY:
This study may provide directions for better characterization of these models and/or identifying new specific therapeutic targets.

TITLE:
Charcot-Marie-Tooth-1A and sciatic nerve crush rat models: insights from proteomics

DESCRIPTION:
The sensorimotor and histological aspects of peripheral neuropathies were already studied by our team in two rat models: the sciatic nerve crush and the Charcot-Marie-Tooth-1A disease. In this study, we sought to highlight and compare the protein signature of these two pathological situations. Indeed, the identification of protein profiles in diseases can play an important role in the development of pharmacological targets. In fact, Charcot-Marie-Tooth-1A rats develop motor impairments that are…

CONTENT:
Neural Regen Res. 2023 Jun;18(6):1354-1363. doi: 10.4103/1673-5374.357911.

ABSTRACT

The sensorimotor and histological aspects of peripheral neuropathies were already studied by our team in two rat models: the sciatic nerve crush and the Charcot-Marie-Tooth-1A disease. In this study, we sought to highlight and compare the protein signature of these two pathological situations. Indeed, the identification of protein profiles in diseases can play an important role in the development of pharmacological targets. In fact, Charcot-Marie-Tooth-1A rats develop motor impairments that are more severe in the hind limbs. Therefore, for the first time, protein expression in sciatic nerve of Charcot-Marie-Tooth-1A rats was examined. First, distal sciatic nerves were collected from Charcot-Marie-Tooth-1A and uninjured wild-type rats aged 3 months. After protein extraction, sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry was employed. 445 proteins mapped to Swiss-Prot or trEMBL Uniprot databases were identified and quantified. Of these, 153 proteins showed statistically significant differences between Charcot-Marie-Tooth-1A and wild-type groups. The majority of these proteins were overexpressed in Charcot-Marie-Tooth-1A. Hierarchical clustering and functional enrichment using Gene Ontology were used to group these proteins based on their biological effects concerning Charcot-Marie-Tooth-1A pathophysiology. Second, proteomic characterization of wild-type rats subjected to sciatic nerve crush was performed sequential window acquisition of all theoretical fragment ion spectra liquid chromatography and mass spectrometry. One month after injury, distal sciatic nerves were collected and analyzed as described above. Out of 459 identified proteins, 92 showed significant differences between sciatic nerve crush and the uninjured wild-type rats used in the first study. The results suggest that young adult Charcot-Marie-Tooth-1A rats (3 months old) develop compensatory mechanisms at the level of redox balance, protein folding, myelination, and axonogenesis. These mechanisms seem insufficient to hurdle the progress of the disease. Notably, response to oxidative stress appears to be a significant feature of Charcot-Marie-Tooth-1A, potentially playing a role in the pathological process. In contrast to the first experiment, the majority of the proteins that differed from wild-type were downregulated in the sciatic nerve crush group. Functional enrichment suggested that neurogenesis, response to axon injury, and oxidative stress were important biological processes. Protein analysis revealed an imperfect repair at this time point after injury and identified several distinguishable proteins. In conclusion, we suggest that peripheral neuropathies, whether of a genetic or traumatic cause, share some common pathological pathways. This study may provide directions for better characterization of these models and/or identifying new specific therapeutic targets.

PMID:36453423 | DOI:10.4103/1673-5374.357911

SOURCE:
Neural regeneration research

TAGS:
This study

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-26T07:51:55Z

DATE – DOI: 2022-11-26T07:51:55Z
DATE – PUBMED:
DATE OUTPUT MATCHED: False

DATE – ADDED:
Thu, 01 Dec 2022 06:00:00 -0500

DATE – RETRIEVED:
12/01/22 07:01AM
2022-12-01T07:01:52-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36453423,doi:10.4103/1673-5374.357911

PUBMED ID:
pubmed:36453423

DOI:
10.4103/1673-5374.357911

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36453423/

LINK – DOI:
https://doi.org/10.4103/1673-5374.357911

LINK – PUBLISHER:
https://journals.lww.com/10.4103/1673-5374.357911

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-12-01T07:01:52-05:00, https://www.cmttreatmentreport.com.

Pathogenic PSAT1 Variants and Autosomal Recessive Axonal Charcot-Marie-Tooth Disease With Ichthyosis

SUMMARY:
Pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

TITLE:
Pathogenic PSAT1 Variants and Autosomal Recessive Axonal Charcot-Marie-Tooth Disease With Ichthyosis

DESCRIPTION:
CONCLUSIONS: Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

CONTENT:
Pediatr Neurol. 2022 Nov 24;140:25-34. doi: 10.1016/j.pediatrneurol.2022.11.013. Online ahead of print.

ABSTRACT

BACKGROUND: Biallelic pathogenic phosphoserine aminotransferase 1 (PSAT1) variants generally cause a severe phenotype predominantly involving the central nervous system. Here, for the first time, we report two patients harboring pathogenic PSAT1 variants only manifested as polyneuropathy and ichthyosis.

METHODS: Two patients from unrelated families presenting with polyneuropathy and ichthyosis were enrolled. Whole exome sequencing was performed to identify possible disease-causing variants. Their clinical, electrophysiological, imaging, biochemical, and pathologic changes were in detail assessed and investigated.

RESULTS: Homozygous variant c.43G>C and compound heterozygous variants c.112A>C and c.43G>C in PSAT1 were identified in patients 1 and 2, respectively. Nerve conduction studies revealed preserved or mild slowing motor nerve conduction velocities of the median nerves in the two patients, whereas the compound motor action potential in patient 1 was severely decreased. Brain magnetic resonance imaging of the two patients found no abnormalities. Median nerve enlargement was observed on ultrasound in patient 1. Both patients had normal level of serine and glycine in plasma and cerebrospinal fluid. Sural nerve biopsy found severe loss of myelinated fibers. Electron microscopy revealed neurofilament accumulation and mitochondrial aggregation in axons. Both variants in PSAT1 were classified as likely pathogenic or pathogenic variants according to the standard guidelines.

CONCLUSIONS: Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

PMID:36599231 | DOI:10.1016/j.pediatrneurol.2022.11.013

SOURCE:
Pediatric neurology

TAGS:
PSAT1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-24T18:25:49Z

DATE – DOI: 2022-11-24T18:25:49Z
DATE – PUBMED: 2022 Nov 24
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 04 Jan 2023 06:00:00 -0500

DATE – RETRIEVED:
01/05/23 01:01AM
2023-01-05T01:01:48-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36599231,doi:10.1016/j.pediatrneurol.2022.11.013

PUBMED ID:
pubmed:36599231

DOI:
10.1016/j.pediatrneurol.2022.11.013

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36599231/

LINK – DOI:
https://doi.org/10.1016/j.pediatrneurol.2022.11.013

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0887899422002454

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-01-05T01:01:48-05:00, https://www.cmttreatmentreport.com.

Clinically relevant mouse models of Charcot-Marie-Tooth Type 2S

SUMMARY:
These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.

TITLE:
Clinically relevant mouse models of Charcot-Marie-Tooth Type 2S

DESCRIPTION:
Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys…

CONTENT:
Hum Mol Genet. 2022 Nov 22:ddac283. doi: 10.1093/hmg/ddac283. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys (Y918C)). E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but does in the Y918C model. Based on these results, the E365del mutant mouse, as well as the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.

PMID:36413117 | DOI:10.1093/hmg/ddac283

SOURCE:
Human molecular genetics

TAGS:
SMARD1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-22T14:51:18Z

DATE – DOI: 2022-11-22T14:51:18Z
DATE – PUBMED: 2022 Nov 22
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 22 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/22/22 12:38PM
2022-11-22T12:38:15-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36413117,doi:10.1093/hmg/ddac283

PUBMED ID:
pubmed:36413117

DOI:
10.1093/hmg/ddac283

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36413117/

LINK – DOI:
https://doi.org/10.1093/hmg/ddac283

LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac283/6839995

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-22T12:38:15-05:00, https://www.cmttreatmentreport.com.

Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system

SUMMARY:
Mice can be used to show the pathogenicity of human GJB1 mutations.

TITLE:
Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system

DESCRIPTION:
The X-linked form of Charcot-Marie-Tooth disease (CMTX1) is the second most common form of CMT. In this study we used CRISPR/Cas9 to develop new “knock-in” models of CMTX1 that are more representative of the spectrum of mutations seen with CMTX1 than the Cx32 knockout (KO) mouse model used previously. We compared mice of four genotypes – wild-type, Cx32KO, p.T55I, and p.R75W. Sciatic motor conduction velocity slowing was the most robust electrophysiologic indicator of neuropathy, showing…

CONTENT:
Exp Neurol. 2022 Nov 17:114277. doi: 10.1016/j.expneurol.2022.114277. Online ahead of print.

ABSTRACT

The X-linked form of Charcot-Marie-Tooth disease (CMTX1) is the second most common form of CMT. In this study we used CRISPR/Cas9 to develop new “knock-in” models of CMTX1 that are more representative of the spectrum of mutations seen with CMTX1 than the Cx32 knockout (KO) mouse model used previously. We compared mice of four genotypes – wild-type, Cx32KO, p.T55I, and p.R75W. Sciatic motor conduction velocity slowing was the most robust electrophysiologic indicator of neuropathy, showing reductions in the Cx32KO by 3 months and in the p.T55I and p.R75W mice by 6 months. At both 6 and 12 months, all three mutant genotypes showed reduced four limb and hind limb grip strength compared to WT mice. Performance on 6 and 12 mm width balance beams revealed deficits that were most pronounced at on the 6 mm balance beam at 6 months of age. There were pathological changes of myelinated axons the femoral motor nerve in all three mutant lines by 3 months of age, and these became more pronounced at 6 and 12 months of age; sensory nerves (femoral sensory and the caudal nerve of the tail) appeared normal at all ages examined. Our results demonstrate that mice can be used to show the pathogenicity of human GJB1 mutations, and these new models for CMTX1 should facilitate the preclinical work for developing treatments for CMTX1.

PMID:36403785 | DOI:10.1016/j.expneurol.2022.114277

SOURCE:
Experimental neurology

TAGS:
Mice

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-18T14:07:34Z

DATE – DOI: 2022-11-18T14:07:34Z
DATE – PUBMED: 2022 Nov 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sun, 20 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/21/22 01:00AM
2022-11-21T01:00:16-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36403785,doi:10.1016/j.expneurol.2022.114277

PUBMED ID:
pubmed:36403785

DOI:
10.1016/j.expneurol.2022.114277

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36403785/

LINK – DOI:
https://doi.org/10.1016/j.expneurol.2022.114277

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0014488622003028

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-21T01:00:16-05:00, https://www.cmttreatmentreport.com.

A novel splicing mutation in 5’UTR of GJB1 causes X-linked Charcot-Marie-tooth disease

SUMMARY:
This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

TITLE:
A novel splicing mutation in 5’UTR of GJB1 causes X-linked Charcot-Marie-tooth disease

DESCRIPTION:
CONCLUSION: Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

CONTENT:
Mol Genet Genomic Med. 2022 Nov 17:e2108. doi: 10.1002/mgg3.2108. Online ahead of print.

ABSTRACT

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X-linked CMT disease.

METHODS: In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole-exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF-7 cells by minigene splicing assay.

RESULTS: The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole-exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.-16-8_-14del) in the GJB1 gene. SNP array linkage analysis and co-segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2.

CONCLUSION: Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

PMID:36394156 | DOI:10.1002/mgg3.2108

SOURCE:
Molecular genetics & genomic medicine

TAGS:
GJB1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-17T11:09:38Z

DATE – DOI: 2022-11-17T11:09:38Z
DATE – PUBMED: 2022 Nov 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 17 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/17/22 07:03PM
2022-11-17T19:03:55-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36394156,doi:10.1002/mgg3.2108

PUBMED ID:
pubmed:36394156

DOI:
10.1002/mgg3.2108

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36394156/

LINK – DOI:
https://doi.org/10.1002/mgg3.2108

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/mgg3.2108

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-17T19:03:55-05:00, https://www.cmttreatmentreport.com.

Targeted inactivation of the Septin2 and Septin9 genes in myelinating Schwann cells of mice

SUMMARY:
SEPTIN2 but not SEPTIN9 is required for the formation or stabilization of a septin multimer in PNS myelin in vivo.

TITLE:
Targeted inactivation of the Septin2 and Septin9 genes in myelinating Schwann cells of mice

DESCRIPTION:
The formation of axon-enwrapping myelin sheaths by oligodendrocytes in the central nervous system (CNS) involves the assembly of a scaffolding septin filament comprised of the subunits SEPTIN2, SEPTIN4, SEPTIN7 and SEPTIN8. Conversely, in the peripheral nervous system (PNS) myelin is synthesized by a different cell type termed Schwann cells, and it remained unknown if septins also assemble as a multimer in PNS myelin. According to prior proteome analysis, PNS myelin comprises the subunits…

CONTENT:
Cytoskeleton (Hoboken). 2022 Nov 15. doi: 10.1002/cm.21736. Online ahead of print.

ABSTRACT

The formation of axon-enwrapping myelin sheaths by oligodendrocytes in the central nervous system (CNS) involves the assembly of a scaffolding septin filament comprised of the subunits SEPTIN2, SEPTIN4, SEPTIN7 and SEPTIN8. Conversely, in the peripheral nervous system (PNS) myelin is synthesized by a different cell type termed Schwann cells, and it remained unknown if septins also assemble as a multimer in PNS myelin. According to prior proteome analysis, PNS myelin comprises the subunits SEPTIN2, SEPTIN7, SEPTIN8, SEPTIN9 and SEPTIN11, which localize to the paranodal and abaxonal myelin sub-compartments. Here we use the Cre/loxP-system to delete the Septin9-gene specifically in Schwann cells, causing a markedly reduced abundance of SEPTIN9 in sciatic nerves, implying that Schwann cells are the main cell type expressing SEPTIN9 in the nerve. However, Septin9-deficiency in Schwann cells did not affect the abundance or localization of other septin subunits. In contrast, when deleting the Septin2-gene in Schwann cells the abundance of all relevant septin subunits was markedly reduced, including SEPTIN9. Notably, we did not find evidence that deleting Septin2 or Septin9 in Schwann cells impairs myelin biogenesis, nerve conduction velocity or motor/sensory capabilities, at least at the assessed timepoints. Our data thus show that SEPTIN2 but not SEPTIN9 is required for the formation or stabilization of a septin multimer in PNS myelin in vivo; however, its functional relevance remains to be established. This article is protected by copyright. All rights reserved.

PMID:36378242 | DOI:10.1002/cm.21736

SOURCE:
Cytoskeleton (Hoboken, N.J.)

TAGS:
SEPTIN2 SEPTIN9

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-15T16:33:35Z

DATE – DOI: 2022-11-15T16:33:35Z
DATE – PUBMED: 2022 Nov 15
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 15 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/15/22 01:01PM
2022-11-15T13:01:15-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36378242,doi:10.1002/cm.21736

PUBMED ID:
pubmed:36378242

DOI:
10.1002/cm.21736

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36378242/

LINK – DOI:
https://doi.org/10.1002/cm.21736

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/cm.21736

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-15T13:01:15-05:00, https://www.cmttreatmentreport.com.

A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication

SUMMARY:
The MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

TITLE:
A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication

DESCRIPTION:
Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance…

CONTENT:
PLoS Genet. 2022 Nov 9;18(11):e1010477. doi: 10.1371/journal.pgen.1010477. Online ahead of print.

ABSTRACT

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

PMID:36350884 | DOI:10.1371/journal.pgen.1010477

SOURCE:
PLoS genetics

TAGS:
MpzT124M

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-11-09T19:07:13Z

DATE – DOI: 2022-11-09T19:07:13Z
DATE – PUBMED: 2022 Nov 9
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 09 Nov 2022 06:00:00 -0500

DATE – RETRIEVED:
11/09/22 07:00PM
2022-11-09T19:00:05-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36350884,doi:10.1371/journal.pgen.1010477

PUBMED ID:
pubmed:36350884

DOI:
10.1371/journal.pgen.1010477

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36350884/

LINK – DOI:
https://doi.org/10.1371/journal.pgen.1010477

LINK – PUBLISHER:
https://dx.plos.org/10.1371/journal.pgen.1010477

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-09T19:00:05-05:00, https://www.cmttreatmentreport.com.

Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot-Marie-Tooth disease 4H

SUMMARY:
FRABIN might be a new therapeutic target for CMT4H.

TITLE:
Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot-Marie-Tooth disease 4H

DESCRIPTION:
Charcot Marie Tooth disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H…

CONTENT:
Brain. 2022 Oct 31:awac402. doi: 10.1093/brain/awac402. Online ahead of print.

ABSTRACT

Charcot Marie Tooth disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin figures called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in Schwann Cell myelination, we generated a knock-out mouse model (Fgd4SC-/-), with conditional ablation of Fgd4 in Schwann cells. We show that the specific deletion of FRABIN in Schwann cells leads to aberrant myelination in vitro, in dorsal root ganglia neurons/Schwann cells cocultures as well in vivo, in distal sciatic nerves from Fgd4SC-/- mice. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ERBB2/3 signaling pathway, which is known to ensure a proper level of myelination in the peripheral nervous system. Based on a yeast two- hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that loss of FRABIN impairs endocytic trafficking which may contribute to the defective NRG1 type III/ERBB2/3 signaling and myelination. Using RNA-Seq in vitro, we have identified new potential effectors of the deregulated pathways, such as ERBIN, RAB11FIP2 and MAF, thereby providing cues to understand how FRABIN contributes to proper ERBB2 trafficking or even myelin membrane addition through cholesterol synthesis. Finally, we showed that the reestablishment of proper levels of the NRG1 type III/ERBB2/3 pathway using Niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ERBB2/3 NRG1signaling and myelination and opens future therapeutic strategies based on the modulation of the NRG1 type III/ERBB2/3 pathway to reduce CMT4H pathology and more generally others demyelinating Charcot Marie Tooth disease.

PMID:36314052 | DOI:10.1093/brain/awac402

SOURCE:
Brain : a journal of neurology

TAGS:
FRABIN

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-10-31T08:02:06Z

DATE – DOI: 2022-10-31T08:02:06Z
DATE – PUBMED: 2022 Oct 31
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 31 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/31/22 07:02AM
2022-10-31T07:02:14-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36314052,doi:10.1093/brain/awac402

PUBMED ID:
pubmed:36314052

DOI:
10.1093/brain/awac402

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36314052/

LINK – DOI:
https://doi.org/10.1093/brain/awac402

LINK – PUBLISHER:
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac402/6780917

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-31T07:02:14-04:00, https://www.cmttreatmentreport.com.

Mutations in MYO9B are associated with CMT2 neuropathies and isolated optic atrophy

SUMMARY:
Novel or very rare variants in MYO9B are associated with CMT2 and isolated OA.

TITLE:
Mutations in MYO9B are associated with CMT2 neuropathies and isolated optic atrophy

DESCRIPTION:
CONCLUSION: Novel or very rare variants in MYO9B are associated with CMT2 and isolated OA.

CONTENT:
Eur J Neurol. 2022 Oct 19. doi: 10.1111/ene.15601. Online ahead of print.

ABSTRACT

OBJECTIVE: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders caused by mutations in at least 100 genes. However, approximately 60% of cases with axonal neuropathies (CMT2) still remain without a genetic diagnosis. We aimed at identifying novel disease genes responsible for CMT2.

METHODS: We performed WES and targeted NGS panel analyses on a cohort of CMT2 families with evidence for autosomal recessive inheritance. We also performed functional studies to explore the pathogenetic role of selected variants.

RESULTS: We identified rare, recessive variants in the MYO9B (Myosin IX) gene in two families with CMT2. MYO9B has not been yet associated with a human disease. MYO9B is an unconventional single-headed processive myosin motor protein with signaling properties, and, consistent with this, our results indicate that a variant occurring in the MYO9B motor domain impairs protein expression level and motor activity. Interestingly, a Myo9b-null mouse has degenerating axons in their sciatic nerves and optic nerves, indicating that MYO9B plays an essential role in both PNS and CNS axons, respectively. The degeneration observed in the optic nerve prompted us to screen for MYO9B mutations a cohort of patients with optic atrophy (OA). Consistent with this, we found compound heterozygous variants in one case with isolated OA.

CONCLUSION: Novel or very rare variants in MYO9B are associated with CMT2 and isolated OA.

PMID:36260368 | DOI:10.1111/ene.15601

SOURCE:
European journal of neurology

TAGS:
MYO9B

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-10-19T15:40:27Z

DATE – DOI: 2022-10-19T15:40:27Z
DATE – PUBMED: 2022 Oct 19
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 19 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/19/22 01:03PM
2022-10-19T13:03:07-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36260368,doi:10.1111/ene.15601

PUBMED ID:
pubmed:36260368

DOI:
10.1111/ene.15601

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36260368/

LINK – DOI:
https://doi.org/10.1111/ene.15601

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1111/ene.15601

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-19T13:03:07-04:00, https://www.cmttreatmentreport.com.

Young infants with PMP22 duplication can have minor nerve conduction study abnormalities

SUMMARY:
EDX abnormalities in CMT1A patients may appear late during development.

TITLE:
Young infants with PMP22 duplication can have minor nerve conduction study abnormalities

DESCRIPTION:
Charcot-Marie-Tooth disease type 1A (CMT1A) is related to PMP22 gene duplication. It is characterized at electrodiagnostic testing (EDX) by diffuse homogeneous signs of demyelination, such as velocity slowing and prolonged distal latencies. These abnormalities are less pronounced in infants under two years old, and the possibility of normal nerve conduction studies (NCS) in infants with CMT1A under one year of age has been questioned. We report three infants who displayed normal or almost normal…

CONTENT:
Neurophysiol Clin. 2022 Oct 14:S0987-7053(22)00087-9. doi: 10.1016/j.neucli.2022.09.007. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease type 1A (CMT1A) is related to PMP22 gene duplication. It is characterized at electrodiagnostic testing (EDX) by diffuse homogeneous signs of demyelination, such as velocity slowing and prolonged distal latencies. These abnormalities are less pronounced in infants under two years old, and the possibility of normal nerve conduction studies (NCS) in infants with CMT1A under one year of age has been questioned. We report three infants who displayed normal or almost normal NCS. EDX abnormalities in CMT1A patients may therefore appear late during development. This may affect early EDX diagnosis in infants and should be considered for upcoming clinical trials.

PMID:36253232 | DOI:10.1016/j.neucli.2022.09.007

SOURCE:
Neurophysiologie clinique = Clinical neurophysiology

TAGS:
#CMT1A

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-10-15T03:48:16Z

DATE – DOI: 2022-10-15T03:48:16Z
DATE – PUBMED: 2022 Oct 14
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 17 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/18/22 12:59AM
2022-10-18T00:59:58-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36253232,doi:10.1016/j.neucli.2022.09.007

PUBMED ID:
pubmed:36253232

DOI:
10.1016/j.neucli.2022.09.007

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36253232/

LINK – DOI:
https://doi.org/10.1016/j.neucli.2022.09.007

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0987705322000879

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-18T00:59:58-04:00, https://www.cmttreatmentreport.com.

Disease Progression in CMT related to MPZ Mutations: A Longitudinal Study

SUMMARY:
This article is protected by copyright. All rights reserved.

TITLE:
Disease Progression in CMT related to MPZ Mutations: A Longitudinal Study

DESCRIPTION:
OBJECTIVE: The paucity of longitudinal natural history studies in MPZ-neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ-neuropathies across 13 sites of the Inherited Neuropathy Consortium.

CONTENT:
Ann Neurol. 2022 Oct 6. doi: 10.1002/ana.26518. Online ahead of print.

ABSTRACT

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ-neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ-neuropathies across 13 sites of the Inherited Neuropathy Consortium.

METHODS: Change in Charcot Marie Tooth Examination scores (CMTES) and Rasch modified CMTES (CMTES-R) scores were evaluated using longitudinal regression over a 5-year period in subjects with MPZ-neuropathy. Data from 139 patients with MPZ-neuropathy were examined.

RESULTS: The average baseline CMTES and CMTES-R scores were 10.84 (SD 6.0, range 0 – 28) and 14.60 (SD= 7.56, range 0 – 32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 [mean change from baseline of 0.87 points at 2 years (p=0.008)]. Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy [mean change of 1.30 points, (p=0.016) versus 0.06 points, (p=0.889)]. Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy [mean 2 year change of 1.14 for baseline CMTES 8-14 (p=0.025), versus -0.03 for baseline CMTES 0-7 (p=0.958) and 0.25 for baseline CMTES ≥15 (p=0.6897)]. The progression in patients harboring specific MPZ mutations was highly variable.

INTERPRETATION: CMTES scores are sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ-neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ-neuropathies. This article is protected by copyright. All rights reserved.

PMID:36203352 | DOI:10.1002/ana.26518

SOURCE:
Annals of neurology

TAGS:
This article is protected by copyright All rights reserved This article is protected by copyright All rights reserved

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-10-07T05:41:29Z

DATE – DOI: 2022-10-07T05:41:29Z
DATE – PUBMED: 2022 Oct 6
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 07 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/07/22 07:00AM
2022-10-07T07:00:53-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36203352,doi:10.1002/ana.26518

PUBMED ID:
pubmed:36203352

DOI:
10.1002/ana.26518

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36203352/

LINK – DOI:
https://doi.org/10.1002/ana.26518

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/ana.26518

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-07T07:00:53-04:00, https://www.cmttreatmentreport.com.

Magnetic resonance imaging-based lower limb muscle evaluation in Charcot-Marie-Tooth disease type 1A patients and its correlation with clinical data

SUMMARY:
Our MRI parameters obtained through semiquantitative analyses of muscles significantly correlated with clinical parameters in CMT1A patients, suggesting their potential applicability as imaging markers for clinical severity.

TITLE:
Magnetic resonance imaging-based lower limb muscle evaluation in Charcot-Marie-Tooth disease type 1A patients and its correlation with clinical data

DESCRIPTION:
We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal)…

CONTENT:
Sci Rep. 2022 Oct 5;12(1):16622. doi: 10.1038/s41598-022-21112-8.

ABSTRACT

We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal) for the lower leg. Based on MRI results, the following parameters were calculated for each level and for entire muscles: fat infiltration proportion (FIP), significant fat infiltration proportion (SigFIP), and severe fat infiltration proportion (SevFIP). The relationships between the MRI parameters and clinical data were evaluated using Spearman’s correlation analysis. FIP, SigFIP, and SevFIP measured for entire muscles significantly correlated with Charcot-Marie-Tooth Neuropathy Score (p < 0.001), functional disability scale (p < 0.001), 10-m walk test time (p = 0.0003, 0.0010, and 0.0011), and disease duration (p < 0.001). Similar correlations were demonstrated for FIP, SigFIP, and SevFIP acquired from the lower leg. Our MRI parameters obtained through semiquantitative analyses of muscles significantly correlated with clinical parameters in CMT1A patients, suggesting their potential applicability as imaging markers for clinical severity. PMID:36198750 | DOI:10.1038/s41598-022-21112-8 SOURCE: Scientific reports TAGS: MRI CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2022-10-05T12:06:05Z DATE - DOI: 2022-10-05T12:06:05Z DATE - PUBMED: 2022 Oct 5 DATE OUTPUT MATCHED: True DATE - ADDED: Wed, 05 Oct 2022 06:00:00 -0400 DATE - RETRIEVED: 10/06/22 01:00AM 2022-10-06T01:00:37-04:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:36198750,doi:10.1038/s41598-022-21112-8 PUBMED ID: pubmed:36198750 DOI: 10.1038/s41598-022-21112-8 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/36198750/ LINK - DOI: https://doi.org/10.1038/s41598-022-21112-8 LINK - PUBLISHER: https://www.nature.com/articles/s41598-022-21112-8 REFERENCES: CMT Treatment Report, Urgent Research, 2022-10-06T01:00:37-04:00, https://www.cmttreatmentreport.com.

Quality of life and upper limb disability in Charcot-Marie-Tooth disease: A pilot study

SUMMARY:
The results of our study confirm the usefulness of SF36 in recognizing the impact of upper limb disability in these subjects suggesting its use even in the remote monitoring of physical functioning.

TITLE:
Quality of life and upper limb disability in Charcot-Marie-Tooth disease: A pilot study

DESCRIPTION:
Charcot-Marie-Tooth (CMT) patients present mainly lower limbs disability, with slowly progressive distal muscle weakness and atrophy, but hands impairment is a relevant problem affecting the quality of life (QoL). The evaluation of the upper limb is of primary importance. Often these patients present subclinical disorders or report difficulties in manipulating objects, with little evidence in the most used outcome measures. We aim to investigate the impact of hand impairment in the perceived QoL…

CONTENT:
Front Neurol. 2022 Oct 5;13:964254. doi: 10.3389/fneur.2022.964254. eCollection 2022.

ABSTRACT

Charcot-Marie-Tooth (CMT) patients present mainly lower limbs disability, with slowly progressive distal muscle weakness and atrophy, but hands impairment is a relevant problem affecting the quality of life (QoL). The evaluation of the upper limb is of primary importance. Often these patients present subclinical disorders or report difficulties in manipulating objects, with little evidence in the most used outcome measures. We aim to investigate the impact of hand impairment in the perceived QoL of CMT persons and secondly whether the Disability of Arm, Shoulder and Hand (DASH) scale can be useful in assessing upper limb abilities in CMT. We recruited 23 patients with confirmed genetic diagnosis of CMT. We performed a clinical evaluation with Sollerman Hand Function Test (SHFT), Thumb Opposition Test (TOT) and CMT examination score (CMTES). We completed the clinical assessment with DASH scale and the Short form 36 (SF36) questionnaire for a subjective evaluation of upper limb disability and quality of life. All patients also underwent an instrumental evaluation with a hand-held dynamometer measuring hand grip and tripod pinch and a sensor-engineered glove test (SEGT) to evaluate finger opposition movements in a quantitative spatial-temporal way. As expected, we found significant differences between CMT and control group performances in both clinical and instrumental assessment. Concerning QoL, we found that total score of SF36 and the SF36 Physical Composite Score (PCS) correlate with all clinical and instrumental Outcome Measures (OMs), particularly with Tripod pinch strength and TOT, which are considered major determinants of manual dexterity in CMT. DASH scale correlates with most clinical and instrumental OMs. Not surprisingly, we also found a correlation with DASH work, because CMT affects young patients engaged in work activities. However, we found a low correlation with the TOT and the dynamometer suggesting that DASH may not be the best scale for remote monitoring of upper limb disorders in CMT patients. Nevertheless, the results of our study confirm the usefulness of SF36 in recognizing the impact of upper limb disability in these subjects suggesting its use even in the remote monitoring of physical functioning.

PMID:36277933 | PMC:PMC9581160 | DOI:10.3389/fneur.2022.964254

SOURCE:
Frontiers in neurology

TAGS:
SF36

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-10-05T08:51:15Z

DATE – DOI: 2022-10-05T08:51:15Z
DATE – PUBMED: 2022 Oct 5
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 24 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/24/22 06:58AM
2022-10-24T06:58:26-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36277933,pmc:PMC9581160,doi:10.3389/fneur.2022.964254

PUBMED ID:
pubmed:36277933

DOI:
10.3389/fneur.2022.964254

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36277933/

LINK – DOI:
https://doi.org/10.3389/fneur.2022.964254

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fneur.2022.964254/full

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-24T06:58:26-04:00, https://www.cmttreatmentreport.com.

Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model

SUMMARY:
s. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA.

TITLE:
Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model

DESCRIPTION:
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C, S356N in the HARS catalytic domain cause Charcot Marie Tooth Disease Type 2 W (CMT2W), while RNA-binding domain mutation Y454S causes recessive Usher Syndrome Type IIIB (USH3B). In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog…

CONTENT:
Hum Mol Genet. 2022 Sep 26:ddac239. doi: 10.1093/hmg/ddac239. Online ahead of print.

ABSTRACT

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C, S356N in the HARS catalytic domain cause Charcot Marie Tooth Disease Type 2 W (CMT2W), while RNA-binding domain mutation Y454S causes recessive Usher Syndrome Type IIIB (USH3B). In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog hts1 at high expression levels. CMT2W associated mutations, but not Y454S, resulted in reduced growth. We show mistranslation of histidine to glutamine and threonine in V155G and S356N but not Y330C mutants in yeast. Mistranslating V155G and S356N mutants lead to accumulation of insoluble proteins, which was rescued by histidine. Mutants V133F and Y330C showed the most significant growth defect and decreased HARS abundance in cells. Here, histidine supplementation led to insoluble protein aggregation and further reduced viability, indicating histidine toxicity associated with these mutants. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA. Our data will inform future treatment options for HARS patients, where histidine supplementation may either have a toxic or compensating effect depending on the nature of the causative HARS variant.

PMID:36164730 | DOI:10.1093/hmg/ddac239

SOURCE:
Human molecular genetics

TAGS:
s V133F

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-27T06:48:20Z

DATE – DOI: 2022-09-27T06:48:20Z
DATE – PUBMED: 2022 Sep 26
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 27 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/27/22 06:59AM
2022-09-27T06:59:19-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36164730,doi:10.1093/hmg/ddac239

PUBMED ID:
pubmed:36164730

DOI:
10.1093/hmg/ddac239

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36164730/

LINK – DOI:
https://doi.org/10.1093/hmg/ddac239

LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac239/6717848

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-27T06:59:19-04:00, https://www.cmttreatmentreport.com.

Novel mutations in GJB1 trigger intracellular aggregation and stress granule formation in X-linked Charcot-Marie-Tooth Disease

SUMMARY:
GJB1 variants-induced cell stress and dysfunction.

TITLE:
Novel mutations in GJB1 trigger intracellular aggregation and stress granule formation in X-linked Charcot-Marie-Tooth Disease

DESCRIPTION:
X-linked Charcot-Marie-Tooth Disease type 1(CMT1X) is the second most common form of inherited peripheral neuropathy that is caused by mutations in the gap junction beta-1 (GJB1) gene. Using targeted exome-sequencing, we investigated four CMT families from central-southern China and identified two novel missense variants (p.F31S and p.W44G) and two previously reported variants (p.R220Pfs^(*)23 and p.R164Q) of GJB1. All four probands presented typical early-onset peripheral neuropathy, of which…

CONTENT:
Front Neurosci. 2022 Sep 26;16:972288. doi: 10.3389/fnins.2022.972288. eCollection 2022.

ABSTRACT

X-linked Charcot-Marie-Tooth Disease type 1(CMT1X) is the second most common form of inherited peripheral neuropathy that is caused by mutations in the gap junction beta-1 (GJB1) gene. Using targeted exome-sequencing, we investigated four CMT families from central-southern China and identified two novel missense variants (p.F31S and p.W44G) and two previously reported variants (p.R220Pfs* 23 and p.R164Q) of GJB1. All four probands presented typical early-onset peripheral neuropathy, of which the R220Pfs* 23 carrier also had neurologic manifestations in the central nervous system. We then constructed GJB1 expression vectors and performed cell biological analysis in vitro . Expression of FLAG-tagged GJB1 at various time points after transfection revealed evident protein aggregation with both wild-type and mutant forms, indicated with immunostaining and immunoblotting. Detergent-based sequential fractionation confirmed that all mutants were higher expressed and more prone to aggregate than the wild-type, whereas the R220Pfs* 23 mutant showed the greatest amount of SDS-soluble multimers and monomers among groups. Moreover, intracellular aggregation probably occurs in the endoplasmic reticulum compartment rather than the Golgi apparatus. Gap junction plaques were present in all groups and were only compromised in frameshift mutant. Further evidence reveals significant intracellular stress granule formation induced by mutated GJB1 and impaired cell viability indicative of cytotoxicity of self-aggregates. Together, our findings demonstrate novel GJB1 variants-induced cell stress and dysfunction and provide insights into understanding the pathomechanisms of GJB1-CMTX1 and other related disorders.

PMID:36225735 | PMC:PMC9548587 | DOI:10.3389/fnins.2022.972288

SOURCE:
Frontiers in neuroscience

TAGS:
GJB1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-26T05:23:21Z

DATE – DOI: 2022-09-26T05:23:21Z
DATE – PUBMED: 2022 Sep 26
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 13 Oct 2022 06:00:00 -0400

DATE – RETRIEVED:
10/13/22 07:00AM
2022-10-13T07:00:49-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36225735,pmc:PMC9548587,doi:10.3389/fnins.2022.972288

PUBMED ID:
pubmed:36225735

DOI:
10.3389/fnins.2022.972288

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36225735/

LINK – DOI:
https://doi.org/10.3389/fnins.2022.972288

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fnins.2022.972288/full

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-10-13T07:00:49-04:00, https://www.cmttreatmentreport.com.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry

SUMMARY:
An appreciable proportion of CMT patients shows general distress and depression.

TITLE:
Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry

DESCRIPTION:
CONCLUSIONS: An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

CONTENT:
J Neurol. 2022 Sep 16. doi: 10.1007/s00415-022-11365-8. Online ahead of print.

ABSTRACT

BACKGROUND: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT.

METHODS: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs.

RESULTS: We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment.

CONCLUSIONS: An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

PMID:36114297 | DOI:10.1007/s00415-022-11365-8

SOURCE:
Journal of neurology

TAGS:
CMT An appreciable proportion of CMT patients shows general distress and depression

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-16T16:05:44Z

DATE – DOI: 2022-09-16T16:05:44Z
DATE – PUBMED: 2022 Sep 16
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 16 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/17/22 09:38AM
2022-09-17T09:38:50-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36114297,doi:10.1007/s00415-022-11365-8

PUBMED ID:
pubmed:36114297

DOI:
10.1007/s00415-022-11365-8

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36114297/

LINK – DOI:
https://doi.org/10.1007/s00415-022-11365-8

LINK – PUBLISHER:
https://link.springer.com/10.1007/s00415-022-11365-8

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-17T09:38:50-04:00, https://www.cmttreatmentreport.com.

A Charcot-Marie-Tooth-Causing Mutation in HSPB1 Decreases Cell Adaptation to Repeated Stress by Disrupting Autophagic Clearance of Misfolded Proteins

SUMMARY:
Our findings provide novel insights into the molecular mechanisms of HSPB1S135F-induced selective degeneration of peripheral neurons and perspectives for targeting autophagy as a promising therapeutic strategy for CMT neuropathy.

TITLE:
A Charcot-Marie-Tooth-Causing Mutation in HSPB1 Decreases Cell Adaptation to Repeated Stress by Disrupting Autophagic Clearance of Misfolded Proteins

DESCRIPTION:
Charcot-Marie-Tooth (CMT) disease is the most common inherited neurodegenerative disorder with selective degeneration of peripheral nerves. Despite advances in identifying CMT-causing genes, the underlying molecular mechanism, particularly of selective degeneration of peripheral neurons remains to be elucidated. Since peripheral neurons are sensitive to multiple stresses, we hypothesized that daily repeated stress might be an essential contributor to the selective degeneration of peripheral…

CONTENT:
Cells. 2022 Sep 15;11(18):2886. doi: 10.3390/cells11182886.

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is the most common inherited neurodegenerative disorder with selective degeneration of peripheral nerves. Despite advances in identifying CMT-causing genes, the underlying molecular mechanism, particularly of selective degeneration of peripheral neurons remains to be elucidated. Since peripheral neurons are sensitive to multiple stresses, we hypothesized that daily repeated stress might be an essential contributor to the selective degeneration of peripheral neurons induced by CMT-causing mutations. Here, we mainly focused on the biological effects of the dominant missense mutation (S135F) in the 27-kDa small heat-shock protein HSPB1 under repeated heat shock. HSPB1S135F presented hyperactive binding to both α-tubulin and acetylated α-tubulin during repeated heat shock when compared with the wild type. The aberrant interactions with tubulin prevented microtubule-based transport of heat shock-induced misfolded proteins for the formation of perinuclear aggresomes. Furthermore, the transport of autophagosomes along microtubules was also blocked. These results indicate that the autophagy pathway was disrupted, leading to an accumulation of ubiquitinated protein aggregates and a significant decrease in cell adaptation to repeated stress. Our findings provide novel insights into the molecular mechanisms of HSPB1S135F -induced selective degeneration of peripheral neurons and perspectives for targeting autophagy as a promising therapeutic strategy for CMT neuropathy.

PMID:36139461 | DOI:10.3390/cells11182886

SOURCE:
Cells

TAGS:
HSPB1S135F

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-16T02:40:53Z

DATE – DOI: 2022-09-16T02:40:53Z
DATE – PUBMED: 2022 Sep 15
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 23 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/23/22 07:05AM
2022-09-23T07:05:10-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36139461,doi:10.3390/cells11182886

PUBMED ID:
pubmed:36139461

DOI:
10.3390/cells11182886

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36139461/

LINK – DOI:
https://doi.org/10.3390/cells11182886

LINK – PUBLISHER:
https://www.mdpi.com/2073-4409/11/18/2886

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-23T07:05:10-04:00, https://www.cmttreatmentreport.com.

Effectiveness of a specific physical therapy program for Charcot-Marie-Tooth on sleep quality, pain perception, and nocturnal cramps: a pilot study

SUMMARY:
The health promotion of the volunteers in this study affected by the disease. Our findings may serve as a basis for future research to develop a program focused on the treatment of analgesia, which can improve pain perception and alter the objective quality of sleep.

TITLE:
Effectiveness of a specific physical therapy program for Charcot-Marie-Tooth on sleep quality, pain perception, and nocturnal cramps: a pilot study

DESCRIPTION:
CONCLUSION: Our initial hypothesis was partially corroborated: the improvement in subjective quality of sleep and nocturnal cramps is already beneficial for the health promotion of the volunteers in this study affected by the disease. Our findings may serve as a basis for future research to develop a program focused on the treatment of analgesia, which can improve pain perception and alter the objective quality of sleep.

CONTENT:
Sleep Sci. 2022 Jul-Sep;15(3):326-333. doi: 10.5935/1984-0063.20220058.

ABSTRACT

INTRODUCTION: Chronic pain, nocturnal cramps, and sleep alterations are prevalent symptoms and signals in Charcot-Marie-Tooth disease patients. Sleep and pain are bidirectionally related and physical therapy can improve the binomial sleep and pain/nocturnal cramps. Therefore, we hypothesized that the application of a specific physical therapy program for Charcot-Marie-Tooth disease would improve sleep quality, pain perception, and nocturnal cramps.

MATERIAL AND METHODS: A non-randomized controlled study that included 9 Charcot-Marie-Tooth disease patients (intervention group – physical therapy program) and 8 controls (active control group – booklet on sleep hygiene). The intervention lasted 8 weeks, three sessions per week. The effects were evaluated ten days before (baseline) and ten days after the intervention (post). Our primary outcome was sleep quality (subjective and objective, assessed by Pittsburgh sleep quality index and actigraphy, respectively); and secondary outcomes were pain perception (brief pain inventory) and nocturnal cramps (self-report).

RESULTS: The program was able to improve the subjective sleep quality (p =0.005) and nocturnal cramps (p <0.001) but had no effect on actigraphy data (p >0.05) neither on pain perception (p >0.05).

CONCLUSION: Our initial hypothesis was partially corroborated: the improvement in subjective quality of sleep and nocturnal cramps is already beneficial for the health promotion of the volunteers in this study affected by the disease. Our findings may serve as a basis for future research to develop a program focused on the treatment of analgesia, which can improve pain perception and alter the objective quality of sleep.

PMID:36158726 | PMC:PMC9496488 | DOI:10.5935/1984-0063.20220058

SOURCE:
Sleep science (Sao Paulo, Brazil)

TAGS:
pain perception sleep

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-15T13:07:17Z

DATE – DOI: 2022-09-15T13:07:17Z
DATE – PUBMED:
DATE OUTPUT MATCHED: False

DATE – ADDED:
Mon, 26 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/26/22 07:02PM
2022-09-26T19:02:12-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36158726,pmc:PMC9496488,doi:10.5935/1984-0063.20220058

PUBMED ID:
pubmed:36158726

DOI:
10.5935/1984-0063.20220058

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36158726/

LINK – DOI:
https://doi.org/10.5935/1984-0063.20220058

LINK – PUBLISHER:
https://sleepscience.org.br/details/3330/en-US/effectiveness-of-a-specific-physical-therapy-program-for-charcot-marie-tooth-on-sleep-quality–pain-perception–and-nocturnal-cramps–a-pilot-study

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-26T19:02:12-04:00, https://www.cmttreatmentreport.com.

Identity-by-descent analysis of CMTX3 links three families through a common founder

SUMMARY:
The mutation arose in a common ancestor.

TITLE:
Identity-by-descent analysis of CMTX3 links three families through a common founder

DESCRIPTION:
A large 78 kb insertion from chromosome 8q24.3 into Xq27.1 was identified as the cause of CMTX3 in three families of European descent from Australia (CMT193, CMT180) and New Zealand/United Kingdom (CMT623). Using the relatedness tool XIBD to perform genome-wide identity-by-descent (IBD) analysis on 16 affected individuals from the three families demonstrated they all share the CMTX3 disease locus identical-by-descent, confirming the mutation arose in a common ancestor. Relationship estimation…

CONTENT:
J Hum Genet. 2023 Jan;68(1):47-49. doi: 10.1038/s10038-022-01078-1. Epub 2022 Sep 13.

ABSTRACT

A large 78 kb insertion from chromosome 8q24.3 into Xq27.1 was identified as the cause of CMTX3 in three families of European descent from Australia (CMT193, CMT180) and New Zealand/United Kingdom (CMT623). Using the relatedness tool XIBD to perform genome-wide identity-by-descent (IBD) analysis on 16 affected individuals from the three families demonstrated they all share the CMTX3 disease locus identical-by-descent, confirming the mutation arose in a common ancestor. Relationship estimation from IBD segment data has genetically linked all three families through 6th and 7th degree relatives.

PMID:36100665 | DOI:10.1038/s10038-022-01078-1

SOURCE:
Journal of human genetics

TAGS:
mutation

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-13T04:02:46Z

DATE – DOI: 2022-09-13T04:02:46Z
DATE – PUBMED: 2022 Sep 13
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 13 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
01/06/23 07:07AM
2023-01-06T07:07:18-05:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36100665,doi:10.1038/s10038-022-01078-1

PUBMED ID:
pubmed:36100665

DOI:
10.1038/s10038-022-01078-1

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36100665/

LINK – DOI:
https://doi.org/10.1038/s10038-022-01078-1

LINK – PUBLISHER:
https://www.nature.com/articles/s10038-022-01078-1

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-01-06T07:07:18-05:00, https://www.cmttreatmentreport.com.

Heterozygous Seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease

SUMMARY:
Mutant SerRS proteins are known to impact various molecular and cellular functions.

TITLE:
Heterozygous Seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease

DESCRIPTION:
OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding Seryl-tRNA synthetase 1 (SerRS) for three families affected with CMT.

CONTENT:
Ann Neurol. 2022 Sep 11. doi: 10.1002/ana.26501. Online ahead of print.

ABSTRACT

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding Seryl-tRNA synthetase 1 (SerRS) for three families affected with CMT.

METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of three unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays.

RESULTS: Combined linkage analysis for the three families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the three families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.

INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. This article is protected by copyright. All rights reserved.

PMID:36088542 | DOI:10.1002/ana.26501

SOURCE:
Annals of neurology

TAGS:
Mutant SerRS

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-09-11T07:23:42Z

DATE – DOI: 2022-09-11T07:23:42Z
DATE – PUBMED: 2022 Sep 11
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sun, 11 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/11/22 07:01AM
2022-09-11T07:01:41-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36088542,doi:10.1002/ana.26501

PUBMED ID:
pubmed:36088542

DOI:
10.1002/ana.26501

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36088542/

LINK – DOI:
https://doi.org/10.1002/ana.26501

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/ana.26501

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-11T07:01:41-04:00, https://www.cmttreatmentreport.com.

Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts

SUMMARY:
MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.

TITLE:
Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts

DESCRIPTION:
Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on…

CONTENT:
Hum Mol Genet. 2022 Aug 22:ddac201. doi: 10.1093/hmg/ddac201. Online ahead of print.

ABSTRACT

Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.

PMID:35994048 | DOI:10.1093/hmg/ddac201

SOURCE:
Human molecular genetics

TAGS:
Mfn2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-08-22T14:58:30Z

DATE – DOI: 2022-08-22T14:58:30Z
DATE – PUBMED: 2022 Aug 22
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 22 Aug 2022 06:00:00 -0400

DATE – RETRIEVED:
08/22/22 12:59PM
2022-08-22T12:59:34-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35994048,doi:10.1093/hmg/ddac201

PUBMED ID:
pubmed:35994048

DOI:
10.1093/hmg/ddac201

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35994048/

LINK – DOI:
https://doi.org/10.1093/hmg/ddac201

LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac201/6673214

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-08-22T12:59:34-04:00, https://www.cmttreatmentreport.com.

TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration

SUMMARY:
CMT2-related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

TITLE:
TFG mutation induces haploinsufficiency and drives axonal Charcot-Marie-Tooth disease by causing neurite degeneration

DESCRIPTION:
CONCLUSION: CMT2-related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

CONTENT:
CNS Neurosci Ther. 2022 Aug 19. doi: 10.1111/cns.13943. Online ahead of print.

ABSTRACT

AIMS: TFG-related axonal Charcot-Marie-Tooth (CMT) disease is a late-onset, autosomal dominant, hereditary motor, and sensory neuropathy characterized by slowly progressive weakness and atrophy of the distal muscles. The objective of this study was to determine the common pathogenic mechanism of TFG-related CMT type 2 (CMT2) caused by different mutations and establish a direct association between TFG haploinsufficiency and neurodegeneration.

METHODS: Three individuals carrying the TFG p.G269V mutation but with varying disease durations were studied. The effect of the p.G269V mutation was confirmed by analyzing protein samples extracted from the blood of two individuals. The functional consequences of both CMT2 mutant gene products were evaluated in vitro. The effect of TFG deficiency in the nervous system was examined using zebrafish models and cultured mouse neurons.

RESULTS: Overexpression of p.G269V TFG failed to enhance soluble TFG levels by generating insoluble TFG aggregates. TFG deficiency disrupted neurite outgrowth and induced neuronal apoptosis both in vivo and in vitro and further impaired locomotor capacity in zebrafish, which was consistent with the phenotype in patients. Wnt signaling was activated as a protective factor in response to TFG deficiency.

CONCLUSION: CMT2-related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

PMID:35986567 | DOI:10.1111/cns.13943

SOURCE:
CNS neuroscience & therapeutics

TAGS:
TFG

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-08-20T06:39:39Z

DATE – DOI: 2022-08-20T06:39:39Z
DATE – PUBMED: 2022 Aug 19
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 20 Aug 2022 06:00:00 -0400

DATE – RETRIEVED:
08/20/22 08:59AM
2022-08-20T08:59:04-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35986567,doi:10.1111/cns.13943

PUBMED ID:
pubmed:35986567

DOI:
10.1111/cns.13943

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35986567/

LINK – DOI:
https://doi.org/10.1111/cns.13943

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1111/cns.13943

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-08-20T08:59:04-04:00, https://www.cmttreatmentreport.com.

Implantable Electroceutical Approach Improves Myelination by Restoring Membrane Integrity in a Mouse Model of Peripheral Demyelinating Neuropathy

SUMMARY:
An electroceutical approach with the optimal ES condition has the potential to treat CMT disease and restore impaired myelin membrane integrity.

TITLE:
Implantable Electroceutical Approach Improves Myelination by Restoring Membrane Integrity in a Mouse Model of Peripheral Demyelinating Neuropathy

DESCRIPTION:
Although many efforts are undertaken to treat peripheral demyelinating neuropathies based on biochemical interventions, unfortunately, there is no approved treatment yet. Furthermore, previous studies have not shown improvement of the myelin membrane at the biomolecular level. Here, an electroceutical treatment is introduced as a biophysical intervention to treat Charcot-Marie-Tooth (CMT) disease-the most prevalent peripheral demyelinating neuropathy worldwide-using a mouse model. The specific…

CONTENT:
Adv Sci (Weinh). 2022 Aug 17:e2201358. doi: 10.1002/advs.202201358. Online ahead of print.

ABSTRACT

Although many efforts are undertaken to treat peripheral demyelinating neuropathies based on biochemical interventions, unfortunately, there is no approved treatment yet. Furthermore, previous studies have not shown improvement of the myelin membrane at the biomolecular level. Here, an electroceutical treatment is introduced as a biophysical intervention to treat Charcot-Marie-Tooth (CMT) disease-the most prevalent peripheral demyelinating neuropathy worldwide-using a mouse model. The specific electrical stimulation (ES) condition (50 mV mm-1 , 20 Hz, 1 h) for optimal myelination is found via an in vitro ES screening system, and its promyelinating effect is validated with ex vivo dorsal root ganglion model. Biomolecular investigation via time-of-flight secondary ion mass spectrometry shows that ES ameliorates distribution abnormalities of peripheral myelin protein 22 and cholesterol in the myelin membrane, revealing the restoration of myelin membrane integrity. ES intervention in vivo via flexible implantable electrodes shows not only gradual rehabilitation of mouse behavioral phenotypes (balance and endurance), but also restored myelin thickness, compactness, and membrane integrity. This study demonstrates, for the first time, that an electroceutical approach with the optimal ES condition has the potential to treat CMT disease and restore impaired myelin membrane integrity, shifting the paradigm toward practical interventions for peripheral demyelinating neuropathies.

PMID:35975427 | DOI:10.1002/advs.202201358

SOURCE:
Advanced science (Weinheim, Baden-Wurttemberg, Germany)

TAGS:
electroceutical

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-08-17T07:10:47Z

DATE – DOI: 2022-08-17T07:10:47Z
DATE – PUBMED: 2022 Aug 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 17 Aug 2022 06:00:00 -0400

DATE – RETRIEVED:
08/17/22 07:02AM
2022-08-17T07:02:05-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35975427,doi:10.1002/advs.202201358

PUBMED ID:
pubmed:35975427

DOI:
10.1002/advs.202201358

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35975427/

LINK – DOI:
https://doi.org/10.1002/advs.202201358

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/advs.202201358

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-08-17T07:02:05-04:00, https://www.cmttreatmentreport.com.

Charcot-Marie-Tooth Disease as a Risk Factor for Periprosthetic Fractures in Tibiotalocalcaneal Fusion With Intramedullary Nailing

SUMMARY:
This suggests that CMT is a significant risk factor. The authors propose a longer nail to reduce the lever arm, with a long period of protected weight bearing till union, followed by consideration of elective removal of the nail to prevent this phenomenon from occurring.

TITLE:
Charcot-Marie-Tooth Disease as a Risk Factor for Periprosthetic Fractures in Tibiotalocalcaneal Fusion With Intramedullary Nailing

DESCRIPTION:
Introduction The treatment for severe fixed hindfoot osteoarthritis secondary to Charcot-Marie-Tooth disease (CMT) is tibiotalocalcaneal (TTC) arthrodesis. In our centre, we have noticed a disproportionate rate of periprosthetic fractures in CMT patients following TTC arthrodesis with retrograde hindfoot nailing. The aim of this study was to test this hypothesis by evaluating our local cohort of TTC arthrodesis with retrograde hindfoot nailing. Methods A retrospective review of patients who had…

CONTENT:
Cureus. 2022 Aug 15;14(8):e28036. doi: 10.7759/cureus.28036. eCollection 2022 Aug.

ABSTRACT

Introduction The treatment for severe fixed hindfoot osteoarthritis secondary to Charcot-Marie-Tooth disease (CMT) is tibiotalocalcaneal (TTC) arthrodesis. In our centre, we have noticed a disproportionate rate of periprosthetic fractures in CMT patients following TTC arthrodesis with retrograde hindfoot nailing. The aim of this study was to test this hypothesis by evaluating our local cohort of TTC arthrodesis with retrograde hindfoot nailing. Methods A retrospective review of patients who had TTC arthrodesis with intramedullary nailing was conducted over a seven-year period. Results There were 45 patients (30 male, 15 female) in our cohort. Forty-one patients achieved radiological and clinical fusion of their TTC arthrodesis. All three patients who had CMT sustained periprosthetic fracture at the tip of the nail at an average of four (range: 2.5-6) months from index operation. In comparison, no patients in the rest of the cohort sustained periprosthetic fractures. The nail position of the patients with CMT was central in both planes in all three patients. None of the patients with CMT had abutment of the cortex on either plane. Conclusion We found that there was a disproportionate rate of periprosthetic fractures in CMT patients in our cohort of TTC arthrodesis with retrograde hindfoot nailing. This suggests that CMT is a significant risk factor. The authors propose a longer nail to reduce the lever arm, with a long period of protected weight bearing till union, followed by consideration of elective removal of the nail to prevent this phenomenon from occurring.

PMID:36120283 | PMC:PMC9473675 | DOI:10.7759/cureus.28036

SOURCE:
Cureus

TAGS:
CMT

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-08-15T19:35:22Z

DATE – DOI: 2022-08-15T19:35:22Z
DATE – PUBMED: 2022 Aug 15
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 19 Sep 2022 06:00:00 -0400

DATE – RETRIEVED:
09/19/22 06:59AM
2022-09-19T06:59:06-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:36120283,pmc:PMC9473675,doi:10.7759/cureus.28036

PUBMED ID:
pubmed:36120283

DOI:
10.7759/cureus.28036

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36120283/

LINK – DOI:
https://doi.org/10.7759/cureus.28036

LINK – PUBLISHER:
https://www.cureus.com/articles/106095-charcot-marie-tooth-disease-as-a-risk-factor-for-periprosthetic-fractures-in-tibiotalocalcaneal-fusion-with-intramedullary-nailing

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-09-19T06:59:06-04:00, https://www.cmttreatmentreport.com.

CMT2A-linked mitochondrial hyperfusion-driving mutant MFN2 perturbs ER-mitochondrial associations and Ca2+ homeostasis

SUMMARY:
Presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health.

TITLE:
CMT2A-linked mitochondrial hyperfusion-driving mutant MFN2 perturbs ER-mitochondrial associations and Ca2+ homeostasis

DESCRIPTION:
Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. Here we show that a mutant of MFN2, R364W-MFN2, linked with the Charcot Marie Tooth disease, promotes mitochondrial hyperfusion, alters ER mitochondrial associations at the MAM junctions and perturbs inter-organellar calcium homeostasis. Such hyperfused…

CONTENT:
Biol Cell. 2022 Aug 4. doi: 10.1111/boc.202100098. Online ahead of print.

ABSTRACT

Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. Here we show that a mutant of MFN2, R364W-MFN2, linked with the Charcot Marie Tooth disease, promotes mitochondrial hyperfusion, alters ER mitochondrial associations at the MAM junctions and perturbs inter-organellar calcium homeostasis. Such hyperfused mitochondria are also predisposed towards stress and undergo rapid fission upon induction of mild stress. Thus, here we report that presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health. This article is protected by copyright. All rights reserved.

PMID:35924634 | DOI:10.1111/boc.202100098

SOURCE:
Biology of the cell

TAGS:
R364WMFN2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-08-04T09:28:57Z

DATE – DOI: 2022-08-04T09:28:57Z
DATE – PUBMED: 2022 Aug 4
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 04 Aug 2022 06:00:00 -0400

DATE – RETRIEVED:
08/04/22 12:15PM
2022-08-04T12:15:07-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35924634,doi:10.1111/boc.202100098

PUBMED ID:
pubmed:35924634

DOI:
10.1111/boc.202100098

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35924634/

LINK – DOI:
https://doi.org/10.1111/boc.202100098

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1111/boc.202100098

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-08-04T12:15:07-04:00, https://www.cmttreatmentreport.com.

A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism

SUMMARY:
The MPZD61N/+ mouse represents an authentic model of severe CMT1B affirming gain-of-glycosylation in P0 as a novel pathomechanism of disease.

TITLE:
A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism

DESCRIPTION:
Mutations in the Myelin Protein Zero gene (MPZ), encoding P0, the major structural glycoprotein of peripheral nerve myelin, are the cause of Charcot-Marie-Tooth (CMT) type 1B neuropathy, and most P0 mutations appear to act through gain-of-function mechanisms. Here we investigated how misglycosylation, a pathomechanism encompassing several genetic disorders, may affect P0 function. Using in vitro assays, we showed that gain of glycosylation is more damaging for P0 trafficking and functionality as…

CONTENT:
Hum Mol Genet. 2022 Jul 31:ddac170. doi: 10.1093/hmg/ddac170. Online ahead of print.

ABSTRACT

Mutations in the Myelin Protein Zero gene (MPZ), encoding P0, the major structural glycoprotein of peripheral nerve myelin, are the cause of Charcot-Marie-Tooth (CMT) type 1B neuropathy, and most P0 mutations appear to act through gain-of-function mechanisms. Here we investigated how misglycosylation, a pathomechanism encompassing several genetic disorders, may affect P0 function. Using in vitro assays, we showed that gain of glycosylation is more damaging for P0 trafficking and functionality as compared to loss of glycosylation. Hence, we generated, via CRISPR/Cas9, a mouse model carrying the MPZD61N mutation, predicted to generate a new N-glycosylation site in P0. In humans, MPZD61N causes a severe early onset form of CMT1B, suggesting that hyperglycosylation may interfere with myelin formation, leading to pathology. We show here that MPZD61N/+ mice develop a tremor as early as P15 which worsens with age and correlates with a significant motor impairment, reduced muscular strength and with substantial alterations in neurophysiology. Pathological analysis confirmed a dysmyelinating phenotype characterized by diffuse hypomyelination and focal hypermyelination. We find that the mutant P0D61N does not cause significant endoplasmic reticulum stress, a common pathomechanism in CMT1B, but is properly trafficked to myelin where it causes myelin uncompaction. Finally, we show that myelinating DRG cultures from MPZD61N mice replicate some of the abnormalities seen in vivo, suggesting that they may represent a valuable tool to investigate therapeutic approaches. Collectively our data indicate that the MPZD61N/+ mouse represents an authentic model of severe CMT1B affirming gain-of-glycosylation in P0 as a novel pathomechanism of disease.

PMID:35908287 | DOI:10.1093/hmg/ddac170

SOURCE:
Human molecular genetics

TAGS:
MPZD61N

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-31T18:19:57Z

DATE – DOI: 2022-07-31T18:19:57Z
DATE – PUBMED: 2022 Jul 31
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sun, 31 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/31/22 07:42PM
2022-07-31T19:42:50-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35908287,doi:10.1093/hmg/ddac170

PUBMED ID:
pubmed:35908287

DOI:
10.1093/hmg/ddac170

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35908287/

LINK – DOI:
https://doi.org/10.1093/hmg/ddac170

LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac170/6652577

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-31T19:42:50-04:00, https://www.cmttreatmentreport.com.

Expanding the phenotypic variability of MORC2 gene mutations: from Charcot Marie tooth disease to late-onset pure motor neuropathy

SUMMARY:
MORC2 mutations are associated with autosomal dominant CMT and with adult late onset proximal motor neuropathy.

TITLE:
Expanding the phenotypic variability of MORC2 gene mutations: from Charcot Marie tooth disease to late-onset pure motor neuropathy

DESCRIPTION:
MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN…

CONTENT:
Hum Mutat. 2022 Jul 29. doi: 10.1002/humu.24445. Online ahead of print.

ABSTRACT

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.Gly444Arg and p.His446Gln in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset proximal motor neuropathy, further increasing the spectrum of clinical manifestations associated with MORC2 mutations. This article is protected by copyright. All rights reserved.

PMID:35904125 | DOI:10.1002/humu.24445

SOURCE:
Human mutation

TAGS:
MORC2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-29T10:09:41Z

DATE – DOI: 2022-07-29T10:09:41Z
DATE – PUBMED: 2022 Jul 29
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 29 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/29/22 01:51PM
2022-07-29T13:51:35-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35904125,doi:10.1002/humu.24445

PUBMED ID:
pubmed:35904125

DOI:
10.1002/humu.24445

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35904125/

LINK – DOI:
https://doi.org/10.1002/humu.24445

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/humu.24445

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-29T13:51:35-04:00, https://www.cmttreatmentreport.com.

Advantages of Adult Mouse Dorsal Root Ganglia Explant Culture in Investigating Myelination in an Inherited Neuropathic Mice Model

SUMMARY:
A DRG explant culture is a scientifically, ethically, and economically more practical option than a co-culture system for studying myelin dynamics, myelin sheath formation, and demyelinating disease.

TITLE:
Advantages of Adult Mouse Dorsal Root Ganglia Explant Culture in Investigating Myelination in an Inherited Neuropathic Mice Model

DESCRIPTION:
A co-culture of neurons and Schwann cells has frequently been used to investigate myelin sheath formation. However, this approach is restricted to myelin-related diseases of the peripheral nervous system. This study introduces and compares an ex vivo model of adult-mouse-derived dorsal root ganglia (DRG) explant, with an in vitro co-culture of dissociated neurons from mouse embryo DRG and Schwann cells from a mouse sciatic nerve. The 2D co-culture has disadvantages of different mouse isolation…

CONTENT:
Methods Protoc. 2022 Jul 22;5(4):66. doi: 10.3390/mps5040066.

ABSTRACT

A co-culture of neurons and Schwann cells has frequently been used to investigate myelin sheath formation. However, this approach is restricted to myelin-related diseases of the peripheral nervous system. This study introduces and compares an ex vivo model of adult-mouse-derived dorsal root ganglia (DRG) explant, with an in vitro co-culture of dissociated neurons from mouse embryo DRG and Schwann cells from a mouse sciatic nerve. The 2D co-culture has disadvantages of different mouse isolation for neurons and Schwann cells, animal number, culture duration, and the identification of disease model. However, 3D DRG explant neurons and myelination cells in Matrigel-coated culture are obtained from the same mouse, the culture period is shorter than that of 2D co-culture, and fewer animals are needed. In addition, it has simpler and shorter experimental steps than 2D co-culture. This culture system may prove advantageous in studies of biological functions and pathophysiological mechanisms of disease models, since it can reflect disease characteristics as traditional co-culture does. Therefore, it is suggested that a DRG explant culture is a scientifically, ethically, and economically more practical option than a co-culture system for studying myelin dynamics, myelin sheath formation, and demyelinating disease.

PMID:35893592 | DOI:10.3390/mps5040066

SOURCE:
Methods and protocols

TAGS:
DRG

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-25T06:16:00Z

DATE – DOI: 2022-07-25T06:16:00Z
DATE – PUBMED: 2022 Jul 22
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 27 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/27/22 07:56AM
2022-07-27T07:56:25-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35893592,doi:10.3390/mps5040066

PUBMED ID:
pubmed:35893592

DOI:
10.3390/mps5040066

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35893592/

LINK – DOI:
https://doi.org/10.3390/mps5040066

LINK – PUBLISHER:
https://www.mdpi.com/2409-9279/5/4/66

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-27T07:56:25-04:00, https://www.cmttreatmentreport.com.

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

SUMMARY:
CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

TITLE:
Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

DESCRIPTION:
Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7^(V162M) mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic…

CONTENT:
Commun Biol. 2022 Jul 18;5(1):717. doi: 10.1038/s42003-022-03632-1.

ABSTRACT

Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs). Primary cultured E18 dorsal root ganglion (DRG) sensory neurons also show mitochondrial fragmentation and altered axonal mitochondrial movement. In addition, we demonstrate that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalize the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study reveals, for the first time, that expression of CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

PMID:35851620 | DOI:10.1038/s42003-022-03632-1

SOURCE:
Communications biology

TAGS:
CMT2B

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-18T14:17:54Z

DATE – DOI: 2022-07-18T14:17:54Z
DATE – PUBMED: 2022 Jul 18
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 19 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/19/22 01:45PM
2022-07-19T13:45:48-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35851620,doi:10.1038/s42003-022-03632-1

PUBMED ID:
pubmed:35851620

DOI:
10.1038/s42003-022-03632-1

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35851620/

LINK – DOI:
https://doi.org/10.1038/s42003-022-03632-1

LINK – PUBLISHER:
https://www.nature.com/articles/s42003-022-03632-1

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-19T13:45:48-04:00, https://www.cmttreatmentreport.com.

C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model

SUMMARY:
CMT2P is a slowly progressive axonal loss.

TITLE:
C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model

DESCRIPTION:
Missense mutation C694R in the RING domain of the LRSAM1 gene results in a dominantly inherited polyneuropathy, Charcot-Marie-Tooth disease type 2P (CMT2P). We have generated and characterized a Lrsam1^(C698R) knock-in mouse model produced through CRISPR/Cas9 technology. Both heterozygous (Lrsam1^(+/C698R)) and homozygous (Lrsam1^(C698/C698R)) knock-in mice exhibited normal motor functions on behavioral tests as well as normal on nerve conduction studies. Axonal density and myelin thickness were…

CONTENT:
Sci Rep. 2022 Jul 16;12(1):12160. doi: 10.1038/s41598-022-15902-3.

ABSTRACT

Missense mutation C694R in the RING domain of the LRSAM1 gene results in a dominantly inherited polyneuropathy, Charcot-Marie-Tooth disease type 2P (CMT2P). We have generated and characterized a Lrsam1C698R knock-in mouse model produced through CRISPR/Cas9 technology. Both heterozygous (Lrsam1+/C698R ) and homozygous (Lrsam1C698/C698R ) knock-in mice exhibited normal motor functions on behavioral tests as well as normal on nerve conduction studies. Axonal density and myelin thickness were not significantly different between mutants and wild-type mice by sciatic nerve morphometric analysis up to 17 months of age. In line with these normal findings, protein-protein interactions between mutant LRSAM1 and RNA-binding proteins (such as FUS and G3BP1) were still present in mouse cells, which differs from the disrupted interactions between these proteins in human CMT2P cells. However, after crush nerve injury, Lrsam1+/C698R mice had a mild, but statistically significant, reduced compound nerve action potential and conduction velocity during recovery. Therefore, C698R mutation results in a mild impaired nerve regeneration in mice. We speculate that repetitive nerve injuries may, at least partially, contribute to the slowly progressive axonal loss in CMT2P.

PMID:35842440 | DOI:10.1038/s41598-022-15902-3

SOURCE:
Scientific reports

TAGS:
CMT2P

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-16T10:16:28Z

DATE – DOI: 2022-07-16T10:16:28Z
DATE – PUBMED: 2022 Jul 16
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 16 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/17/22 01:39AM
2022-07-17T01:39:44-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35842440,doi:10.1038/s41598-022-15902-3

PUBMED ID:
pubmed:35842440

DOI:
10.1038/s41598-022-15902-3

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35842440/

LINK – DOI:
https://doi.org/10.1038/s41598-022-15902-3

LINK – PUBLISHER:
https://www.nature.com/articles/s41598-022-15902-3

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-17T01:39:44-04:00, https://www.cmttreatmentreport.com.

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

SUMMARY:
The ical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations.

TITLE:
Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients

DESCRIPTION:
Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype-phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and…

CONTENT:
Genes (Basel). 2022 Jul 8;13(7):1219. doi: 10.3390/genes13071219.

ABSTRACT

Duplication and deletion of the peripheral myelin protein 22 (PMP22 ) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype-phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22 ) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

PMID:35886002 | DOI:10.3390/genes13071219

SOURCE:
Genes

TAGS:
CMT1E

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-08T16:36:47Z

DATE – DOI: 2022-07-08T16:36:47Z
DATE – PUBMED: 2022 Jul 8
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 27 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/27/22 07:56AM
2022-07-27T07:56:25-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35886002,doi:10.3390/genes13071219

PUBMED ID:
pubmed:35886002

DOI:
10.3390/genes13071219

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35886002/

LINK – DOI:
https://doi.org/10.3390/genes13071219

LINK – PUBLISHER:
https://www.mdpi.com/2073-4425/13/7/1219

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-27T07:56:25-04:00, https://www.cmttreatmentreport.com.

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

SUMMARY:
hAAT might help with the progression of CMT1A.

TITLE:
Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

DESCRIPTION:
Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and…

CONTENT:
Int J Mol Sci. 2022 Jul 3;23(13):7405. doi: 10.3390/ijms23137405.

ABSTRACT

Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3 . Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.

PMID:35806409 | DOI:10.3390/ijms23137405

SOURCE:
International journal of molecular sciences

TAGS:
hAAT

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-07-04T03:12:22Z

DATE – DOI: 2022-07-04T03:12:22Z
DATE – PUBMED: 2022 Jul 3
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 09 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/09/22 09:45AM
2022-07-09T09:45:43-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35806409,doi:10.3390/ijms23137405

PUBMED ID:
pubmed:35806409

DOI:
10.3390/ijms23137405

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35806409/

LINK – DOI:
https://doi.org/10.3390/ijms23137405

LINK – PUBLISHER:
https://www.mdpi.com/1422-0067/23/13/7405

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-09T09:45:43-04:00, https://www.cmttreatmentreport.com.

EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study

SUMMARY:
Therefore, it seemed that the EGR2 mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.

TITLE:
EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study

DESCRIPTION:
CONCLUSION: Therefore, it seemed that the EGR2 mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.

CONTENT:
Clin Neuropathol. 2022 Jun 30. doi: 10.5414/NP301460. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The early growth response 2 gene (EGR2) mutations are associated with a group of hereditary neuropathy, including axonal neuropathy and hypomyelinating neuropathy or Charcot-Marie-Tooth disease (CMT) type 1D. We aim to perform an electrodiagnostic, nerve imaging, and histological study of EGR2-associated neuropathy.

MATERIALS AND METHODS: We performed a retrospective analysis of two patients with EGR2-related neurology at our hospital. The neuropathy was confirmed by the nerve conduction study. Nerve imaging and sural biopsies were performed in two patients.

RESULTS: Two unrelated boys exhibited early-onset length-dependent neuropathy. Next generation sequencing identified EGR2 gene with previously described E412K mutation in the third zine finger domain in patient 1 and a previously undescribed variant D355N mutation in the first zinc finger domain in patient 2. The magnetic resonance imaging of the lumbosacral plexus showed no abnormalities in patient 1 and thickened lumbosacral plexuses in patient 2. Electrophysiology and nerve biopsies showed a prominent axonal neuropathy, accompanied with demyelinating involvement.

CONCLUSION: Therefore, it seemed that the EGR2 mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.

PMID:35770518 | DOI:10.5414/NP301460

SOURCE:
Clinical neuropathology

TAGS:
EGR2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-30T08:04:57Z

DATE – DOI: 2022-06-30T08:04:57Z
DATE – PUBMED: 2022 Jun 30
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 30 Jun 2022 06:00:00 -0400

DATE – RETRIEVED:
06/30/22 07:02AM
2022-06-30T07:02:09-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35770518,doi:10.5414/NP301460

PUBMED ID:
pubmed:35770518

DOI:
10.5414/NP301460

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35770518/

LINK – DOI:
https://doi.org/10.5414/NP301460

LINK – PUBLISHER:
https://www.dustri.com/index.php?id=8&artId=189563&doi=10.5414/NP301460

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-30T07:02:09-04:00, https://www.cmttreatmentreport.com.

The role of BAG3 in dilated cardiomyopathy and its association with Charcot-Marie-Tooth disease type 2

SUMMARY:
The IPV motif in protein aggregation by analyzing a potential association between DCM and CMT2.

TITLE:
The role of BAG3 in dilated cardiomyopathy and its association with Charcot-Marie-Tooth disease type 2

DESCRIPTION:
Bcl2-associated athanogene 3 (BAG3) is a multifunctional cochaperone responsible for protein quality control within cells. BAG3 interacts with chaperones HSPB8 and Hsp70 to transport misfolded proteins to the Microtubule Organizing Center (MTOC) and degrade them in autophagosomes in a process known as Chaperone Assisted Selective Autophagy (CASA). Mutations in the second conserved IPV motif of BAG3 are known to cause Dilated Cardiomyopathy (DCM) by inhibiting adequate removal of non-native…

CONTENT:
Acta Myol. 2022 Jun 30;41(2):59-75. doi: 10.36185/2532-1900-071. eCollection 2022 Jun.

ABSTRACT

Bcl2-associated athanogene 3 (BAG3) is a multifunctional cochaperone responsible for protein quality control within cells. BAG3 interacts with chaperones HSPB8 and Hsp70 to transport misfolded proteins to the Microtubule Organizing Center (MTOC) and degrade them in autophagosomes in a process known as Chaperone Assisted Selective Autophagy (CASA). Mutations in the second conserved IPV motif of BAG3 are known to cause Dilated Cardiomyopathy (DCM) by inhibiting adequate removal of non-native proteins. The proline 209 to leucine (P209L) BAG3 mutant in particular causes the aggregation of BAG3 and misfolded proteins as well as the sequestration of essential chaperones. The exact mechanisms of protein aggregation in DCM are unknown. However, the similar presence of insoluble protein aggregates in Charcot-Marie-Tooth disease type 2 (CMT2) induced by the proline 182 to leucine (P182L) HSPB1 mutant points to a possible avenue for future research: IPV motif. In this review, we summarize the molecular mechanisms of CASA and the currently known pathological effects of mutated BAG3 in DCM. Additionally, we will provide insight on the importance of the IPV motif in protein aggregation by analyzing a potential association between DCM and CMT2.

PMID:35832504 | PMC:PMC9237749 | DOI:10.36185/2532-1900-071

SOURCE:
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology

TAGS:
DCM CMT2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-28T08:09:57Z

DATE – DOI: 2022-06-28T08:09:57Z
DATE – PUBMED: 2022 Jun 30
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 14 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/14/22 07:35AM
2022-07-14T07:35:38-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35832504,pmc:PMC9237749,doi:10.36185/2532-1900-071

PUBMED ID:
pubmed:35832504

DOI:
10.36185/2532-1900-071

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35832504/

LINK – DOI:
https://doi.org/10.36185/2532-1900-071

LINK – PUBLISHER:

The role of BAG3 in dilated cardiomyopathy and its association with Charcot-Marie-Tooth disease type 2

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-14T07:35:38-04:00, https://www.cmttreatmentreport.com.

Accelerate Clinical Trials in Charcot-Marie-Tooth Disease (ACT-CMT): A Protocol to Address Clinical Trial Readiness in CMT1A

SUMMARY:
The study will examine novel and existing clinical outcome assessments and motor and sensory biomarkers.

TITLE:
Accelerate Clinical Trials in Charcot-Marie-Tooth Disease (ACT-CMT): A Protocol to Address Clinical Trial Readiness in CMT1A

DESCRIPTION:
With therapeutic trials on the horizon for Charcot-Marie-Tooth type 1A (CMT1A), reliable, valid, and responsive clinical outcome assessments and biomarkers are essential. Accelerate Clinical Trials in CMT (ACT-CMT) is an international study designed to address important gaps in CMT1A clinical trial readiness including the lack of a validated, responsive functional outcome measure for adults, and a lack of validated biomarkers for multicenter application in clinical trials in CMT1A. The primary…

CONTENT:
Front Neurol. 2022 Jun 27;13:930435. doi: 10.3389/fneur.2022.930435. eCollection 2022.

ABSTRACT

With therapeutic trials on the horizon for Charcot-Marie-Tooth type 1A (CMT1A), reliable, valid, and responsive clinical outcome assessments and biomarkers are essential. Accelerate Clinical Trials in CMT (ACT-CMT) is an international study designed to address important gaps in CMT1A clinical trial readiness including the lack of a validated, responsive functional outcome measure for adults, and a lack of validated biomarkers for multicenter application in clinical trials in CMT1A. The primary aims of ACT-CMT include validation of the Charcot-Marie-Tooth Functional Outcome Measure, magnetic resonance imaging of intramuscular fat accumulation as a lower limb motor biomarker, and in-vivo reflectance confocal microscopy of Meissner corpuscle sensory receptor density, a sensory biomarker. Initial studies have indicated that these measures are feasible, reliable and valid. A large prospective, multi-site study is necessary to fully validate and examine the responsiveness of these outcome measures in relation to existing outcomes for use in future clinical trials involving individuals with CMT1A. Two hundred 15 adults with CMT1A are being recruited to participate in this prospective, international, multi-center study. Serial assessments, up to 3 years, are performed and include the CMT-FOM, CMT Exam Score-Rasch, Overall Neuropathy Limitations Scale, CMT-Health Index, as well as nerve conduction studies, and magnetic resonance imaging and Meissner corpuscle biomarkers. Correlations using baseline data will be examined for validity. Longitudinal analyses will document the changes in function, intramuscular fat accumulation, Meissner corpuscle sensory receptor density. Lastly, we will use anchor-based and other statistical methods to determine the minimally clinically important change for these clinical outcome assessments and biomarkers in CMT1A. Reliable, and responsive clinical outcome assessments of function and disease progression biomarkers are urgently needed for application in early and late phase clinical trials in CMT1A. The ACT-CMT study protocol will address this need through the prospective, longitudinal, multicenter examination in unprecedented detail of novel and existing clinical outcome assessments and motor and sensory biomarkers, and enhance international clinical trial infrastructure, training and preparedness for future therapeutic trials in CMT and related neuropathies.

PMID:35832173 | PMC:PMC9271780 | DOI:10.3389/fneur.2022.930435

SOURCE:
Frontiers in neurology

TAGS:
study

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-27T05:31:12Z

DATE – DOI: 2022-06-27T05:31:12Z
DATE – PUBMED: 2022 Jun 27
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 14 Jul 2022 06:00:00 -0400

DATE – RETRIEVED:
07/14/22 07:35AM
2022-07-14T07:35:35-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35832173,pmc:PMC9271780,doi:10.3389/fneur.2022.930435

PUBMED ID:
pubmed:35832173

DOI:
10.3389/fneur.2022.930435

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35832173/

LINK – DOI:
https://doi.org/10.3389/fneur.2022.930435

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fneur.2022.930435/full

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-14T07:35:35-04:00, https://www.cmttreatmentreport.com.

Aberrant Neuregulin 1/ErbB Signaling in Charcot-Marie-Tooth Type 4D Disease

SUMMARY:
The demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling.

TITLE:
Aberrant Neuregulin 1/ErbB Signaling in Charcot-Marie-Tooth Type 4D Disease

DESCRIPTION:
Charcot-Marie-Tooth type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by progressive motor and sensory neuropathy. N-myc downstream regulated gene 1 (NDRG1) is the causative gene for CMT4D. Although more CMT4D cases have been reported, the comprehensive molecular mechanism underlying CMT4D remains elusive. Here, we generated a novel knockout mouse model in which the fourth and fifth exons of the Ndrg1 gene were removed. Ndrg1-deficient mice develop early…

CONTENT:
Mol Cell Biol. 2022 Jun 16:e0055921. doi: 10.1128/mcb.00559-21. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by progressive motor and sensory neuropathy. N-myc downstream regulated gene 1 (NDRG1 ) is the causative gene for CMT4D. Although more CMT4D cases have been reported, the comprehensive molecular mechanism underlying CMT4D remains elusive. Here, we generated a novel knockout mouse model in which the fourth and fifth exons of the Ndrg1 gene were removed. Ndrg1 -deficient mice develop early progressive demyelinating neuropathy and limb muscle weakness. The expression pattern of myelination-related transcriptional factors, including SOX10, OCT6, and EGR2, was abnormal in Ndrg1 -deficient mice. We further investigated the activation of the ErbB2/3 receptor tyrosine kinases in Ndrg1 -deficient sciatic nerves, as these proteins play essential roles in Schwann cell myelination. In the absence of NDRG1, although the total ErbB2/3 receptors expressed by Schwann cells were significantly increased, levels of the phosphorylated forms of ErbB2/3 and their downstream signaling cascades were decreased. This change was not associated with the level of the neuregulin 1 ligand, which was increased in Ndrg1 -deficient mice. In addition, the integrin β4 receptor, which interacts with ErbB2/3 and positively regulates neuregulin 1/ErbB signaling, was significantly reduced in the Ndrg1 -deficient nerve. In conclusion, our data suggest that the demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling.

PMID:35708320 | DOI:10.1128/mcb.00559-21

SOURCE:
Molecular and cellular biology

TAGS:
CMT4D

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-16T13:00:33Z

DATE – DOI: 2022-06-16T13:00:33Z
DATE – PUBMED: 2022 Jun 16
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 16 Jun 2022 06:00:00 -0400

DATE – RETRIEVED:
06/16/22 01:32PM
2022-06-16T13:32:35-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35708320,doi:10.1128/mcb.00559-21

PUBMED ID:
pubmed:35708320

DOI:
10.1128/mcb.00559-21

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35708320/

LINK – DOI:
https://doi.org/10.1128/mcb.00559-21

LINK – PUBLISHER:
https://journals.asm.org/doi/10.1128/mcb.00559-21

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-16T13:32:35-04:00, https://www.cmttreatmentreport.com.

Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

SUMMARY:
Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

TITLE:
Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms…

CONTENT:
Biomedicines. 2022 Jun 15;10(6):1418. doi: 10.3390/biomedicines10061418.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22 ) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2 ) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

PMID:35740439 | DOI:10.3390/biomedicines10061418

SOURCE:
Biomedicines

TAGS:
Theophylline

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-16T02:45:50Z

DATE – DOI: 2022-06-16T02:45:50Z
DATE – PUBMED: 2022 Jun 15
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 24 Jun 2022 06:00:00 -0400

DATE – RETRIEVED:
06/24/22 07:40AM
2022-06-24T07:40:52-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35740439,doi:10.3390/biomedicines10061418

PUBMED ID:
pubmed:35740439

DOI:
10.3390/biomedicines10061418

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35740439/

LINK – DOI:
https://doi.org/10.3390/biomedicines10061418

LINK – PUBLISHER:
https://www.mdpi.com/2227-9059/10/6/1418

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-24T07:40:52-04:00, https://www.cmttreatmentreport.com.

Candidate imaging biomarkers for PMP22-related inherited neuropathies

SUMMARY:
MTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

TITLE:
Candidate imaging biomarkers for PMP22-related inherited neuropathies

DESCRIPTION:
OBJECTIVE: Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose.

CONTENT:
Ann Clin Transl Neurol. 2022 Jun 3. doi: 10.1002/acn3.51561. Online ahead of print.

ABSTRACT

OBJECTIVE: Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose.

METHODS: MRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross-sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTESL ), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter-rater reliability and test-retest repeatability were established for each imaging metric.

RESULTS: Significant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank-sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTESL : p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%).

INTERPRETATION: MTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

PMID:35656877 | DOI:10.1002/acn3.51561

SOURCE:
Annals of clinical and translational neurology

TAGS:
MTR CSA circularity

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-06-03T09:45:04Z

DATE – DOI: 2022-06-03T09:45:04Z
DATE – PUBMED: 2022 Jun 3
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 03 Jun 2022 06:00:00 -0400

DATE – RETRIEVED:
06/03/22 07:09AM
2022-06-03T07:09:24-04:00

FEATURED IMAGE:
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IDENTIFIER:
pmid:35656877,doi:10.1002/acn3.51561

PUBMED ID:
pubmed:35656877

DOI:
10.1002/acn3.51561

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35656877/

LINK – DOI:
https://doi.org/10.1002/acn3.51561

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/acn3.51561

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-03T07:09:24-04:00, https://www.cmttreatmentreport.com.

Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation

SUMMARY:
MRI findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

TITLE:
Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation

DESCRIPTION:
CONCLUSIONS: We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

CONTENT:
Genes Genomics. 2022 May 24. doi: 10.1007/s13258-022-01253-w. Online ahead of print.

ABSTRACT

BACKGROUND: Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C.

OBJECTIVE: This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features.

METHODS: In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients.

RESULTS: We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected.

CONCLUSIONS: We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

PMID:35608774 | DOI:10.1007/s13258-022-01253-w

SOURCE:
Genes & genomics

TAGS:
MRI

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-24T09:22:10Z

DATE – DOI: 2022-05-24T09:22:10Z
DATE – PUBMED: 2022 May 24
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 24 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/24/22 01:05PM
2022-05-24T13:05:05-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35608774,doi:10.1007/s13258-022-01253-w

PUBMED ID:
pubmed:35608774

DOI:
10.1007/s13258-022-01253-w

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35608774/

LINK – DOI:
https://doi.org/10.1007/s13258-022-01253-w

LINK – PUBLISHER:
https://link.springer.com/10.1007/s13258-022-01253-w

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-24T13:05:05-04:00, https://www.cmttreatmentreport.com.

Disruption of endosomal sorting in Schwann cells leads to defective myelination and endosomal abnormalities observed in Charcot-Marie-Tooth disease

SUMMARY:
Demyelinating CMT might be caused by defective endosomal trafficking of internalized cell surface receptors.

TITLE:
Disruption of endosomal sorting in Schwann cells leads to defective myelination and endosomal abnormalities observed in Charcot-Marie-Tooth disease

DESCRIPTION:
Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth disease (CMT), encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous…

CONTENT:
J Neurosci. 2022 May 18:JN-RM-2481-21. doi: 10.1523/JNEUROSCI.2481-21.2022. Online ahead of print.

ABSTRACT

Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth disease (CMT), encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally-impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slowed nerve conduction velocities, delayed myelination and hypomyelinated axons, all of which occur in demyelinating forms of CMT. Consistent with a delay in Schwann cell maturation, HGS-deficient sciatic nerves displayed increased mRNA levels for several promyelinating genes and decreased mRNA levels for genes that serve as markers of myelinating Schwann cells. Loss of HGS also altered the abundance and activation of the ERBB2/3 receptors which are essential for Schwann cell development. We therefore hypothesize that HGS plays a critical role in endosomal sorting of the ERBB2/3 receptors during Schwann cell maturation, which further implicates endosomal dysfunction in inherited peripheral neuropathies.SIGNIFICANCE STATEMENT Schwann cells myelinate peripheral axons, and defects in Schwann cell function cause inherited demyelinating peripheral neuropathies known as CMT. Although many CMT-linked mutations are in genes that encode putative endosomal proteins, little is known about the requirements of endosomal sorting during myelination. In this study, we demonstrate that loss of HGS disrupts the endosomal sorting pathway in Schwann cells, resulting in hypomyelination, aberrant myelin sheaths, and impairment of the ERBB2/3 receptor pathway. These findings suggest that defective endosomal trafficking of internalized cell surface receptors may be a common mechanism contributing to demyelinating CMT.

PMID:35589390 | DOI:10.1523/JNEUROSCI.2481-21.2022

SOURCE:
The Journal of neuroscience : the official journal of the Society for Neuroscience

TAGS:
Demyelinating CMT

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-23T16:23:15Z

DATE – DOI: 2022-05-23T16:23:15Z
DATE – PUBMED: 2022 May 18
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 19 May 2022 06:00:00 -0400

DATE – RETRIEVED:
06/15/22 02:48AM
2022-06-15T02:48:52-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35589390,doi:10.1523/JNEUROSCI.2481-21.2022

PUBMED ID:
pubmed:35589390

DOI:
10.1523/JNEUROSCI.2481-21.2022

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35589390/

LINK – DOI:
https://doi.org/10.1523/JNEUROSCI.2481-21.2022

LINK – PUBLISHER:
https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.2481-21.2022

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-15T02:48:52-04:00, https://www.cmttreatmentreport.com.

A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

SUMMARY:
AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.

TITLE:
A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

DESCRIPTION:
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene…

CONTENT:
J Clin Invest. 2022 May 17:e159814. doi: 10.1172/JCI159814. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using novel artificial microRNAs targeting human and mouse PMP22/Pmp22 mRNAs. Our lead therapeutic microRNA, miR871, was packaged into an AAV9 vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22/Pmp22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. Treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.

PMID:35579942 | DOI:10.1172/JCI159814

SOURCE:
The Journal of clinical investigation

TAGS:
AAV9miR871driven silencing of PMP22

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-17T16:25:13Z

DATE – DOI: 2022-05-17T16:25:13Z
DATE – PUBMED: 2022 May 17
DATE OUTPUT MATCHED: True

DATE – ADDED:
Tue, 17 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/17/22 05:21PM
2022-05-17T17:21:36-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35579942,doi:10.1172/JCI159814

PUBMED ID:
pubmed:35579942

DOI:
10.1172/JCI159814

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35579942/

LINK – DOI:
https://doi.org/10.1172/JCI159814

LINK – PUBLISHER:
http://www.jci.org/articles/view/159814

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-17T17:21:36-04:00, https://www.cmttreatmentreport.com.

The Lipid-Binding Defective Dynamin 2 Mutant in Charcot-Marie-Tooth Disease Impairs Proper Actin Bundling and Actin Organization in Glomerular Podocytes

SUMMARY:
Dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in HPCs.

TITLE:
The Lipid-Binding Defective Dynamin 2 Mutant in Charcot-Marie-Tooth Disease Impairs Proper Actin Bundling and Actin Organization in Glomerular Podocytes

DESCRIPTION:
Dynamin is an endocytic protein that functions in vesicle formation by scission of invaginated membranes. Dynamin maintains the structure of foot processes in glomerular podocytes by directly and indirectly interacting with actin filaments. However, molecular mechanisms underlying dynamin-mediated actin regulation are largely unknown. Here, biochemical and cell biological experiments were conducted to uncover how dynamin modulates interactions between membranes and actin in human podocytes….

CONTENT:
Front Cell Dev Biol. 2022 May 10;10:884509. doi: 10.3389/fcell.2022.884509. eCollection 2022.

ABSTRACT

Dynamin is an endocytic protein that functions in vesicle formation by scission of invaginated membranes. Dynamin maintains the structure of foot processes in glomerular podocytes by directly and indirectly interacting with actin filaments. However, molecular mechanisms underlying dynamin-mediated actin regulation are largely unknown. Here, biochemical and cell biological experiments were conducted to uncover how dynamin modulates interactions between membranes and actin in human podocytes. Actin-bundling, membrane tubulating, and GTPase activities of dynamin were examined in vitro using recombinant dynamin 2-wild-type (WT) or dynamin 2-K562E, which is a mutant found in Charcot-Marie-Tooth patients. Dynamin 2-WT and dynamin 2-K562E led to the formation of prominent actin bundles with constant diameters. Whereas liposomes incubated with dynamin 2-WT resulted in tubule formation, dynamin 2-K562E reduced tubulation. Actin filaments and liposomes stimulated dynamin 2-WT GTPase activity by 6- and 20-fold, respectively. Actin-filaments, but not liposomes, stimulated dynamin 2-K562E GTPase activity by 4-fold. Self-assembly-dependent GTPase activity of dynamin 2-K562E was reduced to one-third compared to that of dynamin 2-WT. Incubation of liposomes and actin with dynamin 2-WT led to the formation of thick actin bundles, which often bound to liposomes. The interaction between lipid membranes and actin bundles by dynamin 2-K562E was lower than that by dynamin 2-WT. Dynamin 2-WT partially colocalized with stress fibers and actin bundles based on double immunofluorescence of human podocytes. Dynamin 2-K562E expression resulted in decreased stress fiber density and the formation of aberrant actin clusters. Dynamin 2-K562E colocalized with α-actinin-4 in aberrant actin clusters. Reformation of stress fibers after cytochalasin D-induced actin depolymerization and washout was less effective in dynamin 2-K562E-expressing cells than that in dynamin 2-WT. Bis-T-23, a dynamin self-assembly enhancer, was unable to rescue the decreased focal adhesion numbers and reduced stress fiber density induced by dynamin 2-K562E expression. These results suggest that the low affinity of the K562E mutant for lipid membranes, and atypical self-assembling properties, lead to actin disorganization in HPCs. Moreover, lipid-binding and self-assembly of dynamin 2 along actin filaments are required for podocyte morphology and functions. Finally, dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in HPCs.

PMID:35620056 | PMC:PMC9127447 | DOI:10.3389/fcell.2022.884509

SOURCE:
Frontiers in cell and developmental biology

TAGS:
Dynamin 2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-10T08:53:31Z

DATE – DOI: 2022-05-10T08:53:31Z
DATE – PUBMED: 2022 May 10
DATE OUTPUT MATCHED: True

DATE – ADDED:
Fri, 27 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/27/22 07:17AM
2022-05-27T07:17:46-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35620056,pmc:PMC9127447,doi:10.3389/fcell.2022.884509

PUBMED ID:
pubmed:35620056

DOI:
10.3389/fcell.2022.884509

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35620056/

LINK – DOI:
https://doi.org/10.3389/fcell.2022.884509

LINK – PUBLISHER:
https://www.frontiersin.org/articles/10.3389/fcell.2022.884509/full

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-27T07:17:46-04:00, https://www.cmttreatmentreport.com.

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

SUMMARY:
CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

TITLE:
Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly…

CONTENT:
FEBS Open Bio. 2022 May 4. doi: 10.1002/2211-5463.13422. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

PMID:35509130 | DOI:10.1002/2211-5463.13422

SOURCE:
FEBS open bio

TAGS:
GDAP1

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-05T04:37:32Z

DATE – DOI: 2022-05-05T04:37:32Z
DATE – PUBMED: 2022 May 4
DATE OUTPUT MATCHED: True

DATE – ADDED:
Thu, 05 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/05/22 07:18AM
2022-05-05T07:18:13-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35509130,doi:10.1002/2211-5463.13422

PUBMED ID:
pubmed:35509130

DOI:
10.1002/2211-5463.13422

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35509130/

LINK – DOI:
https://doi.org/10.1002/2211-5463.13422

LINK – PUBLISHER:
https://onlinelibrary.wiley.com/doi/10.1002/2211-5463.13422

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-05T07:18:13-04:00, https://www.cmttreatmentreport.com.

Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

SUMMARY:
IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

TITLE:
Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

DESCRIPTION:
Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the…

CONTENT:
Mol Neurobiol. 2022 Apr 30. doi: 10.1007/s12035-022-02838-y. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A, we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analysed by behavioural, neurophysiological, morphological and biochemical measures. Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild-type values. Taken together, our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in amyotrophic lateral sclerosis and multiple sclerosis animal models, these data demonstrate its potential in managing UPR and ER stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases. (Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

PMID:35501630 | DOI:10.1007/s12035-022-02838-y

SOURCE:
Molecular neurobiology

TAGS:
IFB-088

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-05-02T16:29:49Z

DATE – DOI: 2022-05-02T16:29:49Z
DATE – PUBMED: 2022 Apr 30
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 02 May 2022 06:00:00 -0400

DATE – RETRIEVED:
05/03/22 01:21AM
2022-05-03T01:21:41-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35501630,doi:10.1007/s12035-022-02838-y

PUBMED ID:
pubmed:35501630

DOI:
10.1007/s12035-022-02838-y

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35501630/

LINK – DOI:
https://doi.org/10.1007/s12035-022-02838-y

LINK – PUBLISHER:
https://link.springer.com/10.1007/s12035-022-02838-y

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-03T01:21:41-04:00, https://www.cmttreatmentreport.com.

Generation of a human induced pluripotent stem cell (iPSC) line (JUCTCi019-A) from a patient with Charcot-Marie-Tooth disease type 2A2 (CMT2A2) due to a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in MFN2 gene

SUMMARY:
This iPSC line represents an ideal source for disease modelling and drug development of CMT2A2 disease.

TAG:
#CMT2A2

TITLE:
Generation of a human induced pluripotent stem cell (iPSC) line (JUCTCi019-A) from a patient with Charcot-Marie-Tooth disease type 2A2 (CMT2A2) due to a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in MFN2 gene

DESCRIPTION:
Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder characterized by the progressive damage of the peripheral nerves. We generated a human induced pluripotent stem cell (iPSC) line JUCTCi019-A using dermal fibroblasts-derived from a 50-year-old CMT2A2 patient carrying a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in the MFN2 gene. Fibroblasts were reprogrammed by Sendai viruses encoding for the reprogramming factors: OCT4, SOX2, KLF4 and c-MYC….

CONTENT:
Stem Cell Res. 2022 Apr 12;62:102786. doi: 10.1016/j.scr.2022.102786. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder characterized by the progressive damage of the peripheral nerves. We generated a human induced pluripotent stem cell (iPSC) line JUCTCi019-A using dermal fibroblasts-derived from a 50-year-old CMT2A2 patient carrying a heterozygous missense substitution c.2119C > T (p.Arg707Trp) in the MFN2 gene. Fibroblasts were reprogrammed by Sendai viruses encoding for the reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. Characterization showed normal iPSC morphology and karyotype, expression of pluripotency markers and differentiation into three-germ layers. This iPSC line represents an ideal source for disease modelling and drug development of CMT2A2 disease.

PMID:35468369 | DOI:10.1016/j.scr.2022.102786

SOURCE:
Stem cell research

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-04-12T17:59:21Z

DATE – DOI: 2022-04-12T17:59:21Z
DATE – PUBMED: 2022 Apr 12
DATE OUTPUT MATCHED: True

DATE – ADDED:
Mon, 25 Apr 2022 06:00:00 -0400

DATE – RETRIEVED:
04/26/22 01:26AM
2022-04-26T01:26:11-04:00

IDENTIFIER:
pmid:35468369,doi:10.1016/j.scr.2022.102786

PUBMED ID:
pubmed:35468369

DOI:
10.1016/j.scr.2022.102786

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35468369/

LINK – DOI:
https://doi.org/10.1016/j.scr.2022.102786

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S1873506122001350

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-04-26T01:26:11-04:00, https://www.cmttreatmentreport.com.

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

SUMMARY:
PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

TITLE:
Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

DESCRIPTION:
Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to…

CONTENT:
Neuromuscul Disord. 2022 Apr 9:S0960-8966(22)00102-X. doi: 10.1016/j.nmd.2022.04.002. Online ahead of print.

ABSTRACT

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot-Marie-Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells. PMID:35501275 | DOI:10.1016/j.nmd.2022.04.002 SOURCE: Neuromuscular disorders : NMD TAGS: PMP22 CATEGORY: Research SUBCATEGORY: n/a DATE - PUBLISHED: 2022-04-09T06:12:08Z DATE - DOI: 2022-04-09T06:12:08Z DATE - PUBMED: 2022 Apr 9 DATE OUTPUT MATCHED: True DATE - ADDED: Mon, 02 May 2022 06:00:00 -0400 DATE - RETRIEVED: 05/03/22 01:21AM 2022-05-03T01:21:41-04:00 FEATURED IMAGE: Media Uploaded (image/png) IDENTIFIER: pmid:35501275,doi:10.1016/j.nmd.2022.04.002 PUBMED ID: pubmed:35501275 DOI: 10.1016/j.nmd.2022.04.002 LINK - PUBMED: https://pubmed.ncbi.nlm.nih.gov/35501275/ LINK - DOI: https://doi.org/10.1016/j.nmd.2022.04.002 LINK - PUBLISHER: https://linkinghub.elsevier.com/retrieve/pii/S096089662200102X REFERENCES: CMT Treatment Report, Urgent Research, 2022-05-03T01:21:41-04:00, https://www.cmttreatmentreport.com.

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

SUMMARY:
The analysis of the effects of the vehicle itself is an essential and inescapable step to comprehensibly assess the effects and full potential of curcumin treatment for therapeutic purposes.

TAG:
#curcumin

TITLE:
Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

DESCRIPTION:
Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to peripheral-myelin-protein-22 (PMP22) mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol compound obtained from turmeric (Curcuma longa), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin remain elusive….

CONTENT:
Biomolecules. 2022 Mar 29;12(4):515. doi: 10.3390/biom12040515.

ABSTRACT

Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to peripheral-myelin-protein-22 (PMP22) mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol compound obtained from turmeric (Curcuma longa ), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin remain elusive. Here, we propose curcumin as a possible natural treatment capable of enhancing cellular detoxification mechanisms, resulting in an improvement of the neurodegenerative Trembler-J phenotype. Using a refined method for obtaining enriched Schwann cell cultures, we evaluated the neurotherapeutic action of low dose curcumin treatment on the PMP22 expression, and on the chaperones and autophagy/mammalian target of rapamycin (mTOR) pathways in Trembler-J and wild-type genotypes. In wild-type Schwann cells, the action of curcumin resulted in strong stimulation of the chaperone and macroautophagy pathway, whereas the modulation of ribophagy showed a mild effect. However, despite the promising neuroprotective effects for the treatment of neurological diseases, we demonstrate that the action of curcumin in Trembler-J Schwann cells could be impaired due to the irreversible impact of ethanol used as a common curcumin vehicle necessary for administration. These results contribute to expanding our still limited understanding of PMP22 biology in neurobiology and expose the intrinsic lability of the neurodegenerative Trembler-J genotype. Furthermore, they unravel interesting physiological mechanisms of cellular resilience relevant to the pharmacological treatment of the neurodegenerative Tremble J phenotype with curcumin and ethanol. We conclude that the analysis of the effects of the vehicle itself is an essential and inescapable step to comprehensibly assess the effects and full potential of curcumin treatment for therapeutic purposes.

PMID:35454103 | DOI:10.3390/biom12040515

SOURCE:
Biomolecules

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-03-30T02:24:22Z

DATE – DOI: 2022-03-30T02:24:22Z
DATE – PUBMED: 2022 Mar 29
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 23 Apr 2022 06:00:00 -0400

DATE – RETRIEVED:
04/23/22 09:21AM
2022-04-23T09:21:35-04:00

IDENTIFIER:
pmid:35454103,doi:10.3390/biom12040515

PUBMED ID:
pubmed:35454103

DOI:
10.3390/biom12040515

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35454103/

LINK – DOI:
https://doi.org/10.3390/biom12040515

LINK – PUBLISHER:
https://www.mdpi.com/2218-273X/12/4/515

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-04-23T09:21:35-04:00, https://www.cmttreatmentreport.com.

SARM1 Knockout Does Not Rescue Neuromuscular Phenotypes in a Charcot-Marie-Tooth Disease Type 1A Mouse Model

SUMMARY:
The study found that the mice served in CMT1A mice are likely caused primarily by prolonged dysmyelination.

TITLE:
SARM1 Knockout Does Not Rescue Neuromuscular Phenotypes in a Charcot-Marie-Tooth Disease Type 1A Mouse Model

DESCRIPTION:
BACKGROUND AND AIMS: Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice.

CONTENT:
J Peripher Nerv Syst. 2022 Feb 8. doi: 10.1111/jns.12483. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice.

METHODS: CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1 -/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were also evaluated histologically.

RESULTS: Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, SARM1 knockout conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout.

INTERPRETATION: Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

PMID:35137510 | DOI:10.1111/jns.12483

SOURCE:
Journal of the peripheral nervous system : JPNS

TAGS:
#CMT1A

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2022-01-29T01:39:49Z

DATE – DOI: 2022-01-29T01:39:49Z
DATE – PUBMED: 2022 Feb 8
DATE OUTPUT MATCHED: True

DATE – ADDED:
Wed, 09 Feb 2022 06:00:00 -0500

DATE – RETRIEVED:
05/02/22 02:45AM
2022-05-02T02:45:07-04:00

FEATURED IMAGE:
Media Uploaded (image/png)

IDENTIFIER:
pmid:35137510,doi:10.1111/jns.12483

PUBMED ID:
pubmed:35137510

DOI:
10.1111/jns.12483

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35137510/

LINK – DOI:
https://doi.org/10.1111/jns.12483

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0006291X22001309

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-05-02T02:45:07-04:00, https://www.cmttreatmentreport.com.

Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease

SUMMARY:
Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

ALT SUMMARY:

GDF-15, AREG

TITLE:
Cytokines secreted by mesenchymal stem cells reduce demyelination in an animal model of Charcot-Marie-Tooth disease

DESCRIPTION:
CONCLUSIONS: Our findings demonstrated that WJ-MSCs alleviate the demyelinating phenotype of CMT via the secretion of several cytokines. Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

CONTENT:
Biochem Biophys Res Commun. 2022 Jan 29;597:1-7. doi: 10.1016/j.bbrc.2022.01.098. Online ahead of print.

ABSTRACT

INTRODUCTION: Demyelinating Charcot-Marie-Tooth disease (CMT) is caused by mutations in the genes that encode myelinating proteins or their transcription factors. Our study thus sought to assess the therapeutic effects of cytokines secreted from mesenchymal stem cells (MSCs) on this disease.

METHODS: The therapeutic potential of Wharton’s jelly MSCs (WJ-MSCs) and cytokines secreted by WJ-MSCs was evaluated on Schwann cells (SCs) exhibiting demyelination features, as well as a mouse model of demyelinating CMT.

RESULTS: Co-culture with WJ-MSC protected PMP22-overexpressing SCs from apoptotic cell death. Using a cytokine array, the secretion of growth differentiation factor-15 (GDF-15) and amphiregulin (AREG) was found to be elevated in WJ-MSCs when co-incubated with the PMP22-overexpressing SCs. Administration of both cytokines into trembler-J (Tr-J) mice, an animal model of CMT, significantly enhanced motor nerve conduction velocity compared to the control group. More importantly, this treatment alleviated the demyelinating phenotype of Tr-J mice, as demonstrated by an improvement in the mean diameter and g-ratio of the myelinated axons.

CONCLUSIONS: Our findings demonstrated that WJ-MSCs alleviate the demyelinating phenotype of CMT via the secretion of several cytokines. Further elucidation of the underlying mechanisms of GDF-15 and AREG in myelination might provide a robust basis for the development of effective therapies against demyelinating CMT.

PMID:35121177 | DOI:10.1016/j.bbrc.2022.01.098

SOURCE:
Biochemical and biophysical research communications

CATEGORY:
Research

SUBCATEGORY:
Clinically Relevant

DATE – PUBLISHED:
2022-01-29T01:39:49Z

DATE – DOI: 2022-01-29T01:39:49Z
DATE – PUBMED: 2022 Jan 29
DATE OUTPUT MATCHED: True

DATE – ADDED:
Sat, 05 Feb 2022 06:00:00 -0500

DATE – RETRIEVED:
02/06/22 08:55AM
2022-02-06T08:55:55-05:00

IDENTIFIER:
pmid:35121177,doi:10.1016/j.bbrc.2022.01.098

PUBMED ID:
pubmed:35121177

DOI:
10.1016/j.bbrc.2022.01.098

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35121177/

LINK – DOI:
https://doi.org/10.1016/j.bbrc.2022.01.098

LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0006291X22001309

REFERENCES:
CMT Treatment Report, Urgent Research, 2022-02-06T08:55:55-05:00, https://www.cmttreatmentreport.com.

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