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.
Myelin is one of the most exquisite and important features in the nervous system. It allows for the fast and synchronized communication among neurons. This myelin is inordinately rich in lipids, which makes it vulnerable to lipid metabolism disorders. This project focuses on the characterization of one of the mechanisms that contribute to the formation and maintenance of the myelin sheath. Understanding these mechanisms should aid in the development of therapeutic interventions based on the modulation of these systems that could have impacts of neurological disorders such as Multiple Sclerosis and Charcot-Marie-Tooth.
|Heffernan, Corey; Jain, Mohit R; Liu, Tong et al. (2017) Nectin-like 4 Complexes with Choline Transporter-like Protein-1 and Regulates Schwann Cell Choline Homeostasis and Lipid Biogenesis in Vitro. J Biol Chem 292:4484-4498|