Mfn2

SUMMARY:
The feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations is supported by our data.

TITLE:
Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A

DESCRIPTION:
Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type…

CONTENT:
Cell Mol Life Sci. 2023 Nov 25;80(12):373. doi: 10.1007/s00018-023-05018-w.

ABSTRACT

Mitofusin-2 (MFN2) is an outer mitochondrial membrane protein essential for mitochondrial networking in most cells. Autosomal dominant mutations in the MFN2 gene cause Charcot-Marie-Tooth type 2A disease (CMT2A), a severe and disabling sensory-motor neuropathy that impacts the entire nervous system. Here, we propose a novel therapeutic strategy tailored to correcting the root genetic defect of CMT2A. Though mutant and wild-type MFN2 mRNA are inhibited by RNA interference (RNAi), the wild-type protein is restored by overexpressing cDNA encoding functional MFN2 modified to be resistant to RNAi. We tested this strategy in CMT2A patient-specific human induced pluripotent stem cell (iPSC)-differentiated motor neurons (MNs), demonstrating the correct silencing of endogenous MFN2 and replacement with an exogenous copy of the functional wild-type gene. This approach significantly rescues the CMT2A MN phenotype in vitro, stabilizing the altered axonal mitochondrial distribution and correcting abnormal mitophagic processes. The MFN2 molecular correction was also properly confirmed in vivo in the MitoCharc1 CMT2A transgenic mouse model after cerebrospinal fluid (CSF) delivery of the constructs into newborn mice using adeno-associated virus 9 (AAV9). Altogether, our data support the feasibility of a combined RNAi and gene therapy strategy for treating the broad spectrum of human diseases associated with MFN2 mutations.

PMID:38007410 | DOI:10.1007/s00018-023-05018-w

SOURCE:
Cellular and molecular life sciences : CMLS

TAGS:
Mfn2

CATEGORY:
Research

SUBCATEGORY:
n/a

DATE – PUBLISHED:
2023-11-25T17:01:43Z

DATE – DOI: 2023-11-25T17:01:43Z
DATE – PUBMED: 2023 Nov 25
DATE OUTPUT MATCHED: True

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

DATE – RETRIEVED:
11/26/23 07:41AM
2023-11-26T07:41:03-05:00

FEATURED IMAGE:
Media Uploaded (image/jpeg)

IDENTIFIER:
pmid:38007410,doi:10.1007/s00018-023-05018-w

PUBMED ID:
pubmed:38007410

DOI:
10.1007/s00018-023-05018-w

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/38007410/

LINK – DOI:
https://doi.org/10.1007/s00018-023-05018-w

LINK – PUBLISHER:
https://link.springer.com/10.1007/s00018-023-05018-w

REFERENCES:
CMT Treatment Report, Urgent Research, 2023-11-26T07:41:03-05:00, https://www.cmttreatmentreport.com.

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.