Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice

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.