Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination
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DOI：
10.1172/jci72063
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Brites, Pedro
中科院分区：
文献类型：
--
作者：
da Silva, Tiago Ferreira;Eira, Jessica;Brites, Pedro
肢根型点状软骨发育不良（RCDP）是一种以肌张力减退、白内障、异常骨化、运动发育受损和智力残疾为特征的发育障碍。RCDP的潜在病因是醚磷脂生物合成缺乏，其中缩醛磷脂是神经组织和髓鞘中最丰富的形式;然而，缩醛磷脂在外周神经系统中的作用尚不清楚。在这里，我们使用RCDP的小鼠模型，并分析了周围神经中的缩醛磷脂缺乏的后果。我们确定，缩醛磷脂是至关重要的许旺细胞的发育和分化，缩醛磷脂缺陷受损的径向分选，髓鞘形成和髓鞘结构。缩醛磷脂不足导致蛋白激酶B（AKT）磷酸化缺陷和随后的信号传导，导致突变小鼠神经中糖原合成酶激酶3 β（GSK 3 β）的明显激活。用GSK 3 β抑制剂、锂或4-苄基-2-甲基-1，2，4-噻二唑烷-3，5-二酮（TDZD-8）治疗可恢复雪旺细胞缺陷，有效地绕过血浆酶原缺乏。我们的研究结果表明，正确和及时的雪旺氏分化的缩醛磷脂的要求。细胞和髓鞘形成的过程。此外，这些研究确定了一种机制，通过这种机制，缺乏膜磷脂会导致神经病理学，暗示缩醛磷脂是膜和细胞信号传导的调节剂。
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3 beta (GSK3 beta) in nerves of mutant mice. Treatment with GSK3 beta inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann. cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.