mTORC1 signaling inhibitors
Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth.
Nat Commun. 2020 Jun 05;11(1):2835
Authors: Sawade L, Grandi F, Mignanelli M, Patiño-López G, Klinkert K, Langa-Vives F, Di Guardo R, Echard A, Bolino A, Haucke V
In conclusion, our findings suggest an intimate relationship between the synthesis and turnover of PI 3-phosphates mediated by Rab35-associated MTMRs and the activity of late endosomal/lysosomal mTORC1 that crucially controls myelin growth, thereby unraveling a common effector pathway for myelination in the peripheral nervous system. Based on this model it appears that interference with the synthesis of PI 3-phosphates, in particular of PI(3,5)P2 and/or pharmacological perturbation of mTORC1 signaling may represent viable options for the treatment of CMT patients suffering from inherited neuropathies with abnormal myelin growth, e.g. by local administration of mTORC1 or PIKFYVE inhibitors.
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.
PMID: 32503983 [PubMed – as supplied by publisher]
Sawade L, Grandi F, Mignanelli M, Patiño-López G, Klinkert K, Langa-Vives F, Di Guardo R, Echard A, Bolino A, Haucke V