| First Author | Sawade L | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 2835 |
| PubMed ID | 32503983 | Mgi Jnum | J:294178 |
| Mgi Id | MGI:6447980 | Doi | 10.1038/s41467-020-16696-6 |
| Citation | Sawade L, et al. (2020) Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth. Nat Commun 11(1):2835 |
| abstractText | 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. |
