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Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

Abstract : Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth.
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Submitted on : Wednesday, June 17, 2020 - 11:21:18 PM
Last modification on : Thursday, April 7, 2022 - 10:10:41 AM


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Linda Sawade, Federica Grandi, Marianna Mignanelli, Genaro Patiño-López, Kerstin Klinkert, et al.. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.2835. ⟨10.1038/s41467-020-16696-6⟩. ⟨pasteur-02872864⟩



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