RO1NS118020 Research Supplements to Promote Diversity in Health-Related Research

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ABSTRACT Cells have a limited capacity to synthesize choline, thus cells depend on protein transporters to import choline. Choline is used to synthesize phosphatidylcholine, from which structural lipid components of myelin are synthesized. Phosphatidylcholine is also metabolized to generate phosphotidylinositols, whose phosphorylated derivatives are important signaling lipids that regulate myelination. Choline is involved in synthesis of the universal methyl donor, S-adenosylmethionine (SAM) for histone and DNA methylation, thus regulating gene expression. Considering the position of choline at the crossroad for the biosynthesis of phospholipids and epigenetic regulation, we have very little to no understanding of the regulation of choline import and choline- dependent metabolism in myelinating glial cells. Choline transporters for myelin-forming glial cells have not been identified. We have identified choline-like-transporter 1 (CTL1) as an important regulator of Schwann cell myelination. CTL1 deletion in Schwann cells (CTL1sc-KO) results in early onset of focal hyper-myelination in the PNS. Biochemical analysis revealed an overall decrease in choline-derived phospholipids in the myelin. Furthermore, CTL1 loss impaired myelin gene expression and exhibited altered DNA modifications in Schwann cells. Parent grant proposal of this supplement test the hypothesis that CTL1 is a Schwann cell choline transporter. To that end, we are currently testing three aims to determine: 1) whether CTL1 functions as a choline transporter in Schwann cells, 2) whether CTL1 contributes to phosphatidylinositol signaling in the PNS and 3) whether CTL1 loss impact genetic and epigenetic profiles in Schwann cells. Using the available tools and experimental techniques from the parent study, the proposed study in this Research Supplement is designed to test the hypothesis that CTL1 functions as a choline transporter in oligodendrocytes. This is based on previous reports and our recent findings that CTL1 is highly expressed in oligodendrocytes and its expression increased during oligodendrocyte differentiation. Ms Adriana Torres, who will be supported on the supplement funds, will carry on two specific aims that will determine 1) whether CTL1 functions as a choline transporter in oligodendrocytes and 2) whether CTL1-deficiency in vivo impacts oligodendrocyte development and myelination. Results from the study are expected to provide important insights into understanding the function of choline transport and its metabolism in myelin-forming glial cells.