%0 Journal Article %T Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy %+ Brain and Mind Institute [Lausanne, Switzerland] %+ Marseille medical genetics - Centre de génétique médicale de Marseille (MMG) %+ Institut des Neurosciences de Montpellier (INM) %+ Department of Biomedical Sciences [Antwerp, Belgium] (Peripheral Neuropathy Research Group) %+ Institute Born-Bunge [Antwerp, Belgium] %+ Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249) %+ Department of Medical Biochemistry and Biophysics [Stockholm, Sweden] %+ Department of Neuroscience [Stockholm, Sweden] %+ Department of Clinical Neuroscience and Molecular Medicine [Stockholm, Sweden] %+ Centre of Interdisciplinary Electron Microscopy [Lausanne, Switzerland] %+ Information génomique et structurale (IGS) %+ Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV) %A Bernard-Marissal, Nathalie %A van Hameren, Gerben %A Juneja, Manisha %A Pellegrino, Christophe %A Louhivuori, Lauri %A Bartesaghi, Luca %A Rochat, Cylia %A El Mansour, Omar %A Medard, Jean-Jacques %A Croisier, Marie %A Maclachlan, Catherine %A Poirot, Olivier %A Uhlén, Per %A Timmerman, Vincent %A Tricaud, Nicolas %A Schneider, Bernard %A Chrast, Roman %Z This work was supported by Swiss National Science Foundation Grant 310030L_156460/1 (to B.L.S.), ERANET E-Rare FaSMALS Grant 3ER30_160673 (to B.L.S.), a Neuromuscular Research Association Basel grant (to B.L.S., R.C., and N.B.-M), a Swedish StratNeuro program grant (to R.C.), Swedish Research Council Grant 2015-02394 (to R.C.), Labex EpiGenMed (G.v.H.), European Research Council Grant FP7-IDEAS-ERC 311610 (to N.T.), AFM-Téléthon Research Grant 20044 (to N.T. and R.C.), Fund for Scientific Research FWO-Flanders Grants G036814N and G041416N (to V.T.), the Queen Elisabeth Medical Foundation (V.T.), the Association Belge contre les maladies neuromusculaires (M.J.), the Sigrid Jusélius Foundation (L.L.), and Agence Nationale de la Recherche through the Eranet Neuron III program (C.P.). %< avec comité de lecture %@ 0027-8424 %J Proceedings of the National Academy of Sciences of the United States of America %I National Academy of Sciences %P Epub ahead of print %8 2019-01-18 %D 2019 %R 10.1073/pnas.1810932116 %M 30659145 %K Endoplasmic reticulum %K Mitochondria %K CMT2A %K Neuropathy %K Motor and sensory neurons %Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Journal articles %X Mutations in the MFN2 gene Q:9 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 re-ticulum and mitochondria contacts in CMT2A patient-derived fi-broblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with en-doplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly , pharmacological treatments reinforcing endoplasmic retic-ulum-mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results Q:10 highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2. %G English %2 https://amu.hal.science/hal-01991291/document %2 https://amu.hal.science/hal-01991291/file/Bernard-marissal%20et%20al_HAL.pdf %L hal-01991291 %U https://amu.hal.science/hal-01991291 %~ INSERM %~ CNRS %~ UNIV-AMU %~ INM %~ OPENAIRE %~ BS %~ MMG %~ UNIV-MONTPELLIER %~ IGS %~ INMED %~ NEUROMARSEILLE %~ UM-2015-2021