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Start Over Author "Sawade, L." Publisher national academy of sciences
2 results on '"Sawade, L."'

1. Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy

Author

Gaëtan Chicanne, Francesca Bianchi, Linda Sawade, Ivan de Curtis, Ubaldo Del Carro, Yesim Parman, Marta Guerrero-Valero, Roberta Di Guardo, Davide Pareyson, Valeria Alberizzi, Bernard Payrastre, Federica Grandi, Silvia Cipriani, Angelo Schenone, Alessandra Bolino, Volker Haucke, 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., and Bolino, A.

Subjects
Charcot-Marie-Tooth neuropathies, Schwann cells, myelin, myotubularin, phosphoinositides, Animals, Charcot-Marie-Tooth Disease, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Myelin Sheath, Myosin Type II, Phosphatidylinositol Phosphates, Protein Tyrosine Phosphatases, Non-Receptor, rhoA GTP-Binding Protein, Signal Transduction, RHOA, Myotubularin, Knockout, mTORC1, Myelin, Myosin, medicine, Non-Receptor, Cytoskeleton, Multidisciplinary, biology, Chemistry, Myelin outfoldings, Biological Sciences, Cell biology, medicine.anatomical_structure, biology.protein, Signal transduction, Protein Tyrosine Phosphatases
Abstract

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)P(2), with a preference for PtdIns(3,5)P(2). 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)P(2) 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)P(2) 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.

Published
2021

2. Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.

Author

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, and Bolino A

Subjects
Animals, Charcot-Marie-Tooth Disease genetics, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Knockout, Myelin Sheath genetics, Myosin Type II genetics, Myosin Type II metabolism, Phosphatidylinositol Phosphates genetics, Protein Tyrosine Phosphatases, Non-Receptor genetics, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Charcot-Marie-Tooth Disease metabolism, Myelin Sheath metabolism, Phosphatidylinositol Phosphates biosynthesis, Protein Tyrosine Phosphatases, Non-Receptor metabolism, Signal Transduction
Abstract

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 PtdIns3 P and PtdIns(3,5) P 2 , with a preference for PtdIns(3,5) P 2 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) P 2 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) P 2 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., Competing Interests: The authors declare no competing interest.

Published
2021
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