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Altered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy.

ABSTRACT: Mutations in the MFN2 gene encoding Mitofusin 2 lead to the development of Charcot-Marie-Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2^R94Q induces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum-mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

SUBMITTER: Bernard-Marissal N

PROVIDER: S-EPMC6369737 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Altered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy.

Bernard-Marissal Nathalie N van Hameren Gerben G Juneja Manisha M Pellegrino Christophe C Louhivuori Lauri L Bartesaghi Luca L Rochat Cylia C El Mansour Omar O Médard Jean-Jacques JJ Croisier Marie M Maclachlan Catherine C Poirot Olivier O Uhlén Per P Timmerman Vincent V Tricaud Nicolas N Schneider Bernard L BL Chrast Roman R

Proceedings of the National Academy of Sciences of the United States of America 20190118 6

Mutations in the <i>MFN2</i> gene encoding Mitofusin 2 lead to the development of Charcot-Marie-Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2<sup>R94Q</sup> induces distal axonal degeneration in the absence of overt neuronal death ...[more]

PMID: 30659145

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Project description:Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41-46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings--findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Dataset Information

Altered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy.

Publications

Altered interplay between endoplasmic reticulum and mitochondria in Charcot-Marie-Tooth type 2A neuropathy.

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