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Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.
Guerrero-Valero, Marta; Grandi, Federica; Cipriani, Silvia; Alberizzi, Valeria; Di Guardo, Roberta; Chicanne, Gaetan; Sawade, Linda; Bianchi, Francesca; Del Carro, Ubaldo; De Curtis, Ivan; Pareyson, Davide; Parman, Yesim; Schenone, Angelo; Haucke, Volker; Payrastre, Bernard; Bolino, Alessandra.
Afiliação
  • Guerrero-Valero M; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy.
  • Grandi F; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy.
  • Cipriani S; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy.
  • Alberizzi V; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy.
  • Di Guardo R; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy.
  • Chicanne G; Inserm UMR-1048, I2MC, Université Toulouse 3 Paul Sabatier, 31432 Toulouse, France.
  • Sawade L; Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.
  • Bianchi F; Department of Neurology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
  • Del Carro U; Department of Neurology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
  • De Curtis I; Cell Adhesion Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
  • Pareyson D; Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • Parman Y; Istanbul Faculty of Medicine, Neurology Department, Istanbul University, 34390 Istanbul, Turkey.
  • Schenone A; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences, IRCCS Policlinico San Martino, University of Genoa, 16132 Genoa, Italy.
  • Haucke V; Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.
  • Payrastre B; Inserm UMR-1048, I2MC, Université Toulouse 3 Paul Sabatier, 31432 Toulouse, France.
  • Bolino A; Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy; bolino.alessandra@hsr.it.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Article em En | MEDLINE | ID: mdl-33653949
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Doença de Charcot-Marie-Tooth / Fosfatos de Fosfatidilinositol / Proteínas Tirosina Fosfatases não Receptoras / Bainha de Mielina Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Doença de Charcot-Marie-Tooth / Fosfatos de Fosfatidilinositol / Proteínas Tirosina Fosfatases não Receptoras / Bainha de Mielina Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article