Author ORCID Identifier

0000-0001-5048-1736

Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

Babette Fuss

Second Advisor

Pamela Knapp

Third Advisor

James Lister

Fourth Advisor

Gregory Walsh

Fifth Advisor

Yan Zhang

Abstract

LPA, produced by the lysoPLD activity of ATX, binds its cognate receptors and regulates the development of multiple brain cells, including oligodendrocytes (OLGs). OLGs progress through a lineage from precursor (OPC) to early OLG to immature OLG, until finally the cells mature and enwrap axons to enable saltatory conduction and provide trophic support. The studies in this dissertation characterized the receptors LPA4 and LPA6 as inhibitors of OPC differentiation. Western blot analysis of MS patient lesion tissue found a negative correlation between ATX levels and levels of LPA4 and LPA6. A previously created homology model for LPA4 was used to design and prepare compounds to target LPA6. The PRESTO-TANGO GPCR assay system determined two of these compounds to be partial agonists for the non-Edg LPA receptors. Using a developing zebrafish in vivo model as well as in vitro studies in rat primary OLGs, one of these compounds, GL-8-28, inhibited OLG differentiation gene expression. In further studies, siRNA mediated-knockdowns for Lpar6 in the rat primary OLGs were insufficient to disrupt OLG differentiation gene expression. However, triple knockdown of Lpar1, Lpar4 and Lpar6 significantly increased OLG differentiation gene expression. Because knockdowns of Lpar6 failed to reduce transcription of the target gene below 50 percent, we analyzed Lpar6 null mouse brains, and found a modest increase in myelin proteins. Taken together, these studies provide evidence for a novel inhibitory role of these receptors in OLG development, and potentially novel therapeutic targets in the treatment of multiple sclerosis.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

10-12-2020

Available for download on Saturday, October 11, 2025

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