Abstract
AbstractAmyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion inSOD1G93Amice using Crmp1S522A(Ser522→Ala) knock-in (Crmp1ki/ki) mice in which the S522 phosphorylation site was abolished andCrmp1knock-out (Crmp1−/−) mice, respectively.Crmp1ki/ki/SOD1G93Amice showed longer latency to fall in a rotarod test whileCrmp1−/−/SOD1G93Amice showed shorter latency compared withSOD1G93Amice. Survival was prolonged inCrmp1ki/ki/SOD1G93Amice but not inCrmp1−/−/SOD1G93Amice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved inCrmp1ki/ki/SOD1G93Amice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects inCrmp1ki/ki/SOD1G93AandCrmp1−/−/SOD1G93Amice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.
Funder
MEXT | Japan Society for the Promotion of Science
Ministry of Health, Labour and Welfare
GSK Japan Research Grant 2017
Yokohama Foundation for Advanced Medical Science
Grant for Strategic Research Promotion from Yokohama City University
Subject
General Medicine,General Neuroscience
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献