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

Abstract

Amyotrophic 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 (SOD1). We investigated the effects of Crmp1 phosphorylation and depletion inmice using Crmp1(Ser522→Ala) knock-in () mice in which the S522 phosphorylation site was abolished andknock-out () mice, respectively./mice showed longer latency to fall in a rotarod test while/mice showed shorter latency compared withmice. Survival was prolonged in/mice but not in/mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in/mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in/and/mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.