TY - JOUR T1 - Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0133-22.2022 VL - 9 IS - 3 SP - ENEURO.0133-22.2022 AU - Tetsuya Asano AU - Haruko Nakamura AU - Yuko Kawamoto AU - Mikiko Tada AU - Yayoi Kimura AU - Hiroshi Takano AU - Ryoji Yao AU - Hiroya Saito AU - Takuya Ikeda AU - Hiroyasu Komiya AU - Shun Kubota AU - Shunta Hashiguchi AU - Keita Takahashi AU - Misako Kunii AU - Kenichi Tanaka AU - Yoshio Goshima AU - Fumio Nakamura AU - Hideyuki Takeuchi AU - Hiroshi Doi AU - Fumiaki Tanaka Y1 - 2022/05/01 UR - http://www.eneuro.org/content/9/3/ENEURO.0133-22.2022.abstract N2 - 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 (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knock-in (Crmp1ki/ki) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out (Crmp1−/−) mice, respectively. Crmp1ki/ki/SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1−/−/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki/SOD1G93A mice but not in Crmp1−/−/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in Crmp1ki/ki/SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki/SOD1G93A and Crmp1−/−/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS. ER -