Phosphorylation of myelin regulatory factor by PRKG2 mediates demyelination in Huntington's disease

• Type of Material: Article
• Authors: Peng Yin, Jinan University; Yongcheng Pan, Emory University; Yang Weili, Jinan University; Su Yang, Jinan University; Wenjie Wei, Emory University; Xingxing Chen, Emory University; Yan Hong, Emory University; Dazhang Bai, Jinan University; Xiao-Jiang Li, Emory University; Shihua Li, Emory University
• Language: English
• Date: 2020-04-09
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.15252/embr.201949783
• Title of Journal or Parent Work: EMBO REPORTS
• Volume: 21
• Issue: 6
• Start Page: e49783
• End Page: e49783
• Grant/Funding Information: This work was supported by a Research Contract from Teva Pharmaceuticals and grants from the NIH (NS095181) and National Natural Science Foundation of China (81600990, 81830032, 31872779).
• Keywords: GENE-EXPRESSION; MUTANT HUNTINGTIN; Biochemistry & Molecular Biology; oligodendrocytes; MICE; Cell Biology; BRAIN; huntingtin; PRKG2; IRON; NITRIC-OXIDE; GLIAL-CELLS; LAQUINIMOD; PROTEIN; Science & Technology; myelination; MYRF; Life Sciences & Biomedicine; ACTIVATION
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Demyelination is a common pathological feature of a large number of neurodegenerative diseases including multiple sclerosis and Huntington's disease (HD). Laquinimod (LAQ) has been found to have therapeutic effects on multiple sclerosis and HD. However, the mechanism underlying LAQ's therapeutic effects remains unknown. Using HD mice that selectively express mutant huntingtin in oligodendrocytes and show demyelination, we found that LAQ reduces the Ser259 phosphorylation on myelin regulatory factor (MYRF), an oligodendrocyte-specific transcription factor promoting the expression of myelin-associated genes. The reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin-associated genes. We also found that PRKG2, a cGMP-activated protein kinase subunit II, promotes the Ser259-MYRF phosphorylation and that knocking down PRKG2 increased myelin-associated protein's expression in HD mice. Our findings suggest that PRKG2-regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination.