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

Linda Sawade, Federica Grandi, Marianna Mignanelli, Genaro Patiño-López, Kerstin Klinkert, Francina Langa-Vives, Roberta Guardo, Arnaud Echard, Alessandra Bolino () and Volker Haucke ()
Additional contact information
Linda Sawade: Robert-Rössle-Strasse 10
Federica Grandi: IRCCS Ospedale San Raffaele, Via Olgettina 60
Marianna Mignanelli: IRCCS Ospedale San Raffaele, Via Olgettina 60
Genaro Patiño-López: Hospital Infantil de México, Federico Gómez. C.P
Kerstin Klinkert: UMR3691, CNRS, 25–28 rue du Dr Roux
Francina Langa-Vives: Institut Pasteur, 25–28 rue du Dr Roux
Roberta Guardo: IRCCS Ospedale San Raffaele, Via Olgettina 60
Arnaud Echard: UMR3691, CNRS, 25–28 rue du Dr Roux
Alessandra Bolino: IRCCS Ospedale San Raffaele, Via Olgettina 60
Volker Haucke: Robert-Rössle-Strasse 10

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16696-6

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