RT Journal Article
T1 Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy
A1 Grandi, Federica
A1 Cipriani, Silvia
A1 Alberizzi, Valeria
A1 Di Guardo, Roberta
A1 Chicanne, Gaetan
A1 Sawade, Linda
A1 Bianchi, Francesca
A1 Del Carro, Ubaldo
A1 De Curtis, Ivan
A1 Pareyson, Davide
A1 Parman, Yesim
A1 Schenone, Angelo
A1 Haucke, Volker
A1 Payrastre, Bernard
A1 Bolino, Alessandra
A1 Guerrero Valero, Marta
AB Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P2, with a preference for PtdIns(3,5)P2. A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.
PB National Academy of Sciences (PNAS)
YR 2021
FD 2021-03-02
LK https://hdl.handle.net/20.500.14352/133163
UL https://hdl.handle.net/20.500.14352/133163
LA eng
NO Guerrero-Valero M, Grandi F, Cipriani S, et al. Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy. Proc Natl Acad Sci USA 2021;118:e2009469118. https://doi.org/10.1073/pnas.2009469118
DS Docta Complutense
RD 17 abr 2026