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PMP22

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.

Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP [preprint]

https://www.biorxiv.org/content/10.1101/2021.11.08.467756v1.full

In Pmp22tg CMT1A mice, we uncovered that the differentiation defect of Schwann cells is independent from PI3K/Akt/mTOR activity, rendering the pathway insufficient as a therapy target on its own. Thus, while CMT1A pathogenesis is governed by dys-differentiation uncoupled from PI3K/Akt/mTOR signaling, targeting the pathway provides novel proof-of-principle for a therapeutic approach to HNPP.

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: The past, the present and the future

https://www.translationalres.com/article/S1931-5244(20)30175-4/pdf

https://www.ncbi.nlm.nih.gov/pubmed/32693030?dopt=Abstract

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: The past, the present and the future.

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: The past, the present and the future.

Transl Res. 2020 Jul 18;:

Authors: Boutary S, Echaniz-Laguna A, Adams D, Loisel-Duwattez J, Schumacher M, Massaad C, Massaad-Massade L

Abstract

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000. CMT1A represents 60-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22). PMP22 gene is under tight regulation and small changes in its expression influences myelination and affect motor and sensory functions. To date, CMT1A treatment is symptomatic and classic pharmacological options have been disappointing. Here, we review the past, present and future treatment options for CMT1A, with a special emphasis on the highly promising potential of PMP22-targeted small interfering RNA (siRNA) and antisense oligonucleotides (ASO).

PMID: 32693030 [PubMed – as supplied by publisher]

PubMed:32693030

Boutary S, Echaniz-Laguna A, Adams D, Loisel-Duwattez J, Schumacher M, Massaad C, Massaad-Massade L

Direct Relationship Between Increased Expression and Mistrafficking of the Charcot-Marie-Tooth-Associated Protein PMP22

https://www.jbc.org/content/early/2020/07/09/jbc.AC120.014940

https://www.ncbi.nlm.nih.gov/pubmed/32647009?dopt=Abstract

Direct Relationship Between Increased Expression and Mistrafficking of the Charcot-Marie-Tooth-Associated Protein PMP22.

Related Articles

Direct Relationship Between Increased Expression and Mistrafficking of the Charcot-Marie-Tooth-Associated Protein PMP22.

J Biol Chem. 2020 Jul 09;:

Authors: Marinko JT, Carter BD, Sanders CR

Abstract

Charcot-Marie-Tooth disease (CMT) is a neuropathy of the peripheral nervous system that afflicts ~1:2500 people. The most common form of this disease (CMT1A, 1:4000) is associated with duplication of chromosome fragment 17p11.2-12, which results in a third wild-type PMP22 allele. In rodent models overexpressing the peripheral myelin protein 22 (PMP22) protein and in dermal fibroblasts from patients with CMT1A, PMP22 aggregates have been observed. This suggests that overexpression of PMP22 under CMT1A conditions overwhelms the endoplasmic reticulum (ER) quality control, leading to formation of cytotoxic aggregates. In this work, we used a single-cell flow-cytometry trafficking assay to quantitatively examine the relationship between PMP22 expression and trafficking efficiency in individual cells. We observed that as expression of wild-type or disease variants of PMP22 is increased, the amount of intracellular PMP22 increases to a greater extent than the amount of surface-trafficked protein. This was true for both transiently transfected cells as well as PMP22 stable expressing cells. Our results support the notion that overexpression of PMP22 in CMT1A leads to a disproportionate increase in misfolding and mis-trafficking of PMP22, which is likely a contributor to disease pathology and progression.

PMID: 32647009 [PubMed – as supplied by publisher]

PubMed:32647009

Marinko JT, Carter BD, Sanders CR

Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains

https://www.pnas.org/content/117/25/14168

https://www.ncbi.nlm.nih.gov/pubmed/32513719?dopt=Abstract

Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains.

Related Articles

Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains.

Proc Natl Acad Sci U S A. 2020 Jun 08;:

Authors: Marinko JT, Kenworthy AK, Sanders CR

Abstract

The ordered environment of cholesterol-rich membrane nanodomains is thought to exclude many transmembrane (TM) proteins. Nevertheless, some multispan helical transmembrane proteins have been proposed to partition into these environments. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the helical tetraspan peripheral myelin protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for this preference. In contrast, Charcot-Marie-Tooth disease-causing mutations that disrupt the stability of PMP22 tertiary structure reduce or eliminate this preference in favor of the disordered phase. These studies demonstrate that the ordered phase preference of PMP22 derives from global structural features associated with the folded form of this protein, providing a glimpse at the structural factors that promote raft partitioning for multispan helical membrane proteins.

PMID: 32513719 [PubMed – as supplied by publisher]

PubMed:32513719

Marinko JT, Kenworthy AK, Sanders CR

PMP22 is critical in cholesterol metabolism, and this mechanism is likely a contributing factor in PMP22-linked hereditary neuropathies such as Charcot-Marie-Tooth (CMT)

https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.23840

https://www.ncbi.nlm.nih.gov/pubmed/32511821?dopt=Abstract

Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22.

Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22.

Glia. 2020 Jun 08;:

Authors: Zhou Y, Borchelt D, Bauson JC, Fazio S, Miles JR, Tavori H, Notterpek L

Abstract

Abnormalities of the peripheral myelin protein 22 (PMP22) gene, including duplication, deletion and point mutations are a major culprit in Type 1 Charcot-Marie-Tooth (CMT) diseases. The complete absence of PMP22 alters cholesterol metabolism in Schwann cells, which likely contributes to myelination deficits. Here, we examined the subcellular trafficking of cholesterol in distinct models of PMP22-linked neuropathies. In Schwann cells from homozygous Trembler J (TrJ) mice carrying a Leu16Pro mutation, cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level. PMP22 overexpression, which models CMT1A caused by gene duplication, triggered cholesterol sequestration to lysosomes, and reduced ATP-binding cassette transporter-dependent cholesterol efflux. Conversely, lysosomal targeting of cholesterol by U18666A treatment increased wild type (WT)-PMP22 levels in lysosomes. Mutagenesis of a cholesterol recognition motif, or CRAC domain, in human PMP22 lead to increased levels of PMP22 in the ER and Golgi compartments, along with higher cytosolic, and lower membrane-associated cholesterol. Importantly, cholesterol trafficking defects observed in PMP22-deficient Schwann cells were rescued by WT but not CRAC-mutant-PMP22. We also observed that myelination deficits in dorsal root ganglia explants from heterozygous PMP22-deficient mice were improved by cholesterol supplementation. Collectively, these findings indicate that PMP22 is critical in cholesterol metabolism, and this mechanism is likely a contributing factor in PMP22-linked hereditary neuropathies. Our results provide a basis for understanding how altered expression of PMP22 impacts cholesterol metabolism.

PMID: 32511821 [PubMed – as supplied by publisher]

PubMed:32511821

Zhou Y, Borchelt D, Bauson JC, Fazio S, Miles JR, Tavori H, Notterpek L

Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves

https://academic.oup.com/hmg/article-abstract/29/10/1689/5827383?redirectedFrom=fulltext

http://ncbi.nlm.nih.gov/pmc/articles/PMC7322568/

https://www.ncbi.nlm.nih.gov/pubmed/32356557?dopt=Abstract

Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves.

Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves.

Hum Mol Genet. 2020 Apr 30;:

Authors: Pantera H, Hu B, Moiseev D, Dunham C, Rashid J, Moran JJ, Krentz K, Rubinstein CD, Won S, Li J, Svaren J

Abstract

Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. Duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease, CMT type 1A (CMT1A), while the reciprocal deletion of this gene causes a separate neuropathy termed Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). PMP22 is robustly induced in Schwann cells in early postnatal development, and several transcription factors and their cognate regulatory elements have been implicated in coordinating the gene’s proper expression. We previously found that a distal super-enhancer domain was important for Pmp22 expression in vitro, with particular impact on a Schwann cell-specific alternative promoter. Here, we investigate the consequences of deleting this super-enhancer in vivo. We find that loss of the super-enhancer in mice reduces Pmp22 expression throughout development and into adulthood, with greater impact on the Schwann cell-specific promoter. Additionally, these mice display tomacula formed by excessive myelin folding, a pathological hallmark of HNPP, as have been previously observed in heterozygous Pmp22 mice as well as sural biopsies from patients with HNPP. Our findings demonstrate a mechanism by which smaller copy number variations, not including the Pmp22 gene, are sufficient to reduce gene expression and phenocopy a peripheral neuropathy caused by the HNPP-associated deletion encompassing PMP22.

PMID: 32356557 [PubMed – as supplied by publisher]

PubMed:32356557

Pantera H, Hu B, Moiseev D, Dunham C, Rashid J, Moran JJ, Krentz K, Rubinstein CD, Won S, Li J, Svaren J

CMT Research Foundation Funds Shift Pharmaceuticals to Advance Search for CMT1A Treatment — Shift to Develop and Analyze Novel Series of Drugs Designed to Control Expression of PMP22 Gene

https://cmtrf.org/blog/cmt-research-foundation-funds-shift-pharmaceuticals-to-advance-search-for-cmt1a-treatment/

CMT Research Foundation Funds Shift Pharmaceuticals to Advance Search for CMT1A Treatment

Shift to Develop and Analyze Novel Series of Drugs Designed to Control Expression of PMP22 Gene

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure [Preprint]

https://www.biorxiv.org/content/10.1101/2020.01.29.924605v1.full

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure
Benoit Gautier, Helene Hajjar, Sylvia Soares, Jade Berthelot, Marie Deck, Scarlette Abbou, Graham Campbell, Claire-Maelle Fovet, Vlad Schütza, Antoine Jouvenel, Cyril Rivat, Michel Zerah, Virginie François Le Ravazet, Caroline Le Guiner, Patrick Aubourg, View ORCID ProfileRobert Fledrich, View ORCID ProfileNicolas Tricaud
doi: https://doi.org/10.1101/2020.01.29.924605

Regulating PMP22 Expression as a Dosage Sensitive Neuropathy Gene

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305451?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31586623?dopt=Abstract

Regulating PMP22 Expression as a Dosage Sensitive Neuropathy Gene.

Regulating PMP22 Expression as a Dosage Sensitive Neuropathy Gene.

Brain Res. 2019 Oct 03;:146491

Authors: Pantera H, Shy ME, Svaren J

Abstract

Structural variation in the human genome has emerged as a major cause of disease as genomic data have accumulated. One of the most common structural variants associated with human disease causes the heritable neuropathy known as Charcot-Marie-Tooth (CMT) disease type 1A. This 1.4 Mb duplication causes nearly half of the CMT cases that are genetically diagnosed. The PMP22 gene is highly induced in Schwann cells during development, although its precise role in myelin formation and homeostasis is still under active investigation. The PMP22 gene can be considered as a nucleoprotein complex with enzymatic activity to produce the PMP22 transcript, and the complex is allosterically regulated by transcription factors that respond to intracellular signals and epigenomic modifications. The control of PMP22 transcript levels has been one of the major therapeutic targets of therapy development, and this review summarizes those approaches as well as efforts to characterize the regulation of the PMP22 gene.

PMID: 31586623 [PubMed – as supplied by publisher]

PubMed:31586623

Pantera H, Shy ME, Svaren J

Peripheral myelin protein 22 (PMP22) modulates store operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology

http://www.jbc.org/content/early/2019/06/18/jbc.RA118.006248

https://www.ncbi.nlm.nih.gov/pubmed/31213528?dopt=Abstract

Peripheral myelin protein 22 modulates store operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology.

Related Articles

Peripheral myelin protein 22 modulates store operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology.

J Biol Chem. 2019 Jun 18;:

Authors: Vanoye CG, Sakakura M, Follis RM, Trevisan AJ, Narayan M, Li J, Sanders CR, Carter BD

Abstract

Charcot-Marie-Tooth (CMT) disease is a peripheral neuropathy associated with gene duplication and point mutations in the peripheral myelin protein 22 (PMP22) gene. However, the role of PMP22 in Schwann cell physiology and the mechanisms by which PMP22 mutations cause CMT are not well understood. On the basis of homology between PMP22 and proteins associated with modulation of ion channels, we hypothesized that PMP22 alters ion channel activity. Using whole-cell electrophysiology we show here that heterologous PMP22 expression increases the amplitude of currents similar to those ascribed to store- operated calcium (SOC) channels, particularly those involving transient receptor canonical channel 1 (TrpC1). These channels help replenish Ca+2 in the endoplasmic reticulum (ER) following stimulus-induced depletion. Currents with similar properties were recorded in wild type but not pmp22-/- mouse Schwann cells. Heterologous expression of the CMT-associated PMP22_L16P variant, which fails to reach the plasma membrane and localizes to the ER, led to larger currents than wild type PMP22. Similarly, Schwann cells isolated from Trembler J (TrJ; PMP22_L16P) mice had larger currents than wild type littermates. Calcium imaging in live nerves and cultured Schwann cells revealed elevated intracellular Ca+2 in TrJ mice compared with wild type. Moreover, we found that PMP22 co-immunoprecipitated with stromal interaction molecule 1 (STIM1), the Ca+2 sensor SOC channel subunit in the ER. These results suggest that in the ER, PMP22 interacts with STIM1 and increases Ca+2 influx through SOC channels. Excess or mutant PMP22 in the ER may elevate intracellular Ca+2 levels, which could contribute to CMT pathology.

PMID: 31213528 [PubMed – as supplied by publisher]

PubMed:31213528

Vanoye CG, Sakakura M, Follis RM, Trevisan AJ, Narayan M, Li J, Sanders CR, Carter BD

Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A

https://www.jci.org/articles/view/98617

https://www.ncbi.nlm.nih.gov/pubmed/29199996

Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A.

J Clin Invest. 2018 Jan 2;128(1):110-112. doi: 10.1172/JCI98617. Epub 2017 Dec 4.
Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A.
Shy ME.
Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common heritable peripheral neuropathy and results from a duplication on chromosome 17 that results in an extra copy and increased dosage of peripheral myelin protein 22 (PMP22). Zhao et al., in this issue of the JCI, successfully utilized antisense oligonucleotides (ASOs) to reduce PMP22 and ameliorated neuropathy in both mouse and rat models of CMT1A. These data confirm that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A and lay the groundwork for clinical trials in humans afflicted with this chronic, debilitating neurodegenerative disease.

PMID: 29199996 PMCID: PMC5749496 DOI: 10.1172/JCI98617
Free PMC Article

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