Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy
Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy
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DOI：
10.1073/pnas.2009469118
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发表时间：
2021-03-09
影响因子：
11.1
通讯作者：
Bolino, Alessandra
中科院分区：
文献类型：
--
作者：
Guerrero-Valero, Marta;Grandi, Federica;Bolino, Alessandra
Charcot-Marie-Tooth 4 B1型（CMT 4 B1）是一种严重的常染色体隐性脱髓鞘神经病，由肌微管蛋白相关2（MTMR 2）基因的功能丧失突变引起。MTMR 2是普遍表达的催化活性β-磷酸酶，其在体外使3-磷酸肌醇PtdIns 3 P和PtdIns（3，5）P-2去磷酸化，优选PtdIns（3，5）P-2。CMT 4 B1神经病的标志是神经中的髓鞘的冗余环，称为髓鞘外折叠，这可以被认为是出生后发育期间有髓鞘纤维生长改变的结果。MTMR 2的丢失和由此产生的3 '-磷酸肌醇的不平衡如何导致CMT 4 B1尚不清楚。在这里，我们表明，MTMR 2通过调节PtdIns（3，5）P-2水平协调mTORC 1依赖的髓鞘合成和RhoA/肌球蛋白II依赖的细胞骨架动力学，以促进髓鞘膜扩张和纵向髓鞘生长。与此一致，PtdIns（3，5）P-2合成或mTORC 1/RhoA信号传导的药理学抑制改善了CMT 4 B1表型。我们的数据揭示了MTMR 2调节的脂质周转滴定mTORC 1和RhoA信号转导，从而控制髓鞘生长的关键作用。
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.