Choline Transporter-Like proteins and the regulation of lipid metabolism during myelination

摘要 本研究的重点是胆碱转运蛋白CTL1在调节髓鞘形成中的作用。 少突胶质细胞(CNS)和雪旺细胞(PNS)。 胆碱在磷脂酰胆碱的生物合成中很重要，磷脂酰胆碱是髓鞘中的一种主要脂肪。它是 神经鞘蛋白的直接前体是另一种主要的髓鞘脂类，它也参与了体内的稳态 对对启动有直接影响的重要信号成分的调节 髓鞘形成，髓鞘的紧实和髓鞘的维持。 Necl4是PNS髓鞘形成所必需的一种细胞黏附分子。它在动物身上被击倒了 模型诱导形成髓鞘异常，这是夏科-玛丽-牙齿的特征 神经病理学。我们最近发现Necl4与CTL1相互作用，并调节胆碱转运， 动态平衡和下游胆碱衍生物。 目前尚不清楚髓鞘胶质细胞如何在髓鞘形成开始时调节自己的新陈代谢 响应质膜生产所需的高脂需求，而不破坏其他 细胞过程。Necl4/CTL1的相互作用表明CTL1是 监管。 这项建议的总体目标是了解髓鞘形成过程中胆碱运输的调节。 细胞及其去调控对髓鞘形成和维持的影响。

ABSTRACT This proposal focuses on the function of Choline Transporter CTL1 in regulating myelination by oligodendrocytes (CNS) and Schwann cells (PNS). Choline is important in the biosynthesis of phosphatidylcholine, a major lipid in myelin. It is the direct precursor of sphingomyelin, another major myelin lipid, It is also involved in the homeostatic regulation of important signaling components that have a direct implication on the initiation of myelination, the compaction of the myelin sheath and myelin maintenance. Necl4 is a cell adhesion molecule that is required for PNS myelination. Its knockdown in an animal model induces the formation of myelin abnormalities that are the hallmarks of Charcot-Marie-Tooth neuropathologies. We recently found that Necl4 interacts with CTL1, and regulates choline transport, homeostasis, and downstream Choline-derivatives. It is unclear how myelinating glial cells regulate their metabolism at the onset of myelination to respond to the high demand in lipids needed for plasma membrane production, without disrupting other cell processes. The Necl4/CTL1 interaction suggests that CTL1 is an important component of the regulation. The overall goal of this proposal is to understand the regulation of choline transport in myelinating cells, and the impact of its deregulation on myelin formation and maintenance.