气候变化领域集成服务门户(CCPortal): Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy

CCPortal

DOI	10.1073/pnas.2009469118
	Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy
	Guerrero-Valero M.; Grandi F.; Cipriani S.; Alberizzi V.; Di Guardo R.; Chicanne G.; Sawade L.; Bianchi F.; Del Carro U.; De Curtis I.; Pareyson D.; Parman Y.; Schenone A.; Haucke V.; Payrastre B.; Bolino A.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180372
作者单位	Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale San Raffaele, Milan, 20132, Italy; Inserm UMR-1048, I2MC, Université Toulouse, 3 Paul Sabatier, Toulouse, 31432, France; Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, 13125, Germany; Department of Neurology, IRCCS Ospedale San Raffaele, Milan, 20132, Italy; Cell Adhesion Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, 20132, Italy; Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy; Istanbul Faculty of Medicine, Neurology Department, Istanbul University, Istanbul, 34390, Turkey; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences, IRCCS Policlinico San Martino, University of Ge...
推荐引用方式 GB/T 7714	Guerrero-Valero M.,Grandi F.,Cipriani S.,et al. Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy[J],2021,118(10).
APA	Guerrero-Valero M..,Grandi F..,Cipriani S..,Alberizzi V..,Di Guardo R..,...&Bolino A..(2021).Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Guerrero-Valero M.,et al."Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).