MICE LACKING Gpr37 EXHIBIT DECREASED EXPRESSION OF THE MYELIN-ASSOCIATED GLYCOPROTEIN MAG AND INCREASED SUSCEPTIBILITY TO DEMYELINATION

• Type of Material: Article
• Authors: Brilee M. Smith, Emory University; Michelle M. Giddens, Emory University; Jessica Neil, Neurorepair Therapeutics, Inc.; Sharon Owino, Emory University; TrangKimberly T. Nguyen, Emory University; Duc Duong, Emory University; Fengqiao Li, Neurorepair Therapeutics, Inc.; Randy A Hall, Emory University
• Language: English
• Date: 2017-09-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2017.06.006
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 358
• Start Page: 49
• End Page: 57
• Grant/Funding Information: Research reported in this publication was also supported in part by the Emory Neuroscience NINDS Core Facilities and NIH/NINDS under award number P30NS055077.; This work was funded by the National Multiple Sclerosis Society Fast Forward Program and grant R01-NS088413 from the National Institutes of Health to RAH.
• Keywords: CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; PEPTIDE RECEPTOR; PROTEIN-COUPLED RECEPTORS; Neurosciences & Neurology; REMYELINATION; cuprizone; GPCR; OLIGODENDROCYTES; MOLECULAR-CLONING; remyelination; PARKINSONS-DISEASE; myelin; Life Sciences & Biomedicine; Science & Technology; Neurosciences; multiple sclerosis; BRAIN; PAEL RECEPTOR; demyelination
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology

Abstract

GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). These studies revealed that one of the proteins most sharply decreased in the brains of Gpr37/Gpr37L1 double knockout mice is the myelin-associated glycoprotein MAG. Follow-up Western blot studies confirmed this finding and demonstrated that genetic deletion of Gpr37, but not Gpr37L1, results in strikingly decreased brain expression of MAG. Further in vitro studies demonstrated that GPR37 and MAG form a complex when expressed together in cells. As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37−/−) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37−/−mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis.