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

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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.