RT Journal Article SR Electronic T1 Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0133-22.2022 DO 10.1523/ENEURO.0133-22.2022 VO 9 IS 3 A1 Tetsuya Asano A1 Haruko Nakamura A1 Yuko Kawamoto A1 Mikiko Tada A1 Yayoi Kimura A1 Hiroshi Takano A1 Ryoji Yao A1 Hiroya Saito A1 Takuya Ikeda A1 Hiroyasu Komiya A1 Shun Kubota A1 Shunta Hashiguchi A1 Keita Takahashi A1 Misako Kunii A1 Kenichi Tanaka A1 Yoshio Goshima A1 Fumio Nakamura A1 Hideyuki Takeuchi A1 Hiroshi Doi A1 Fumiaki Tanaka YR 2022 UL http://www.eneuro.org/content/9/3/ENEURO.0133-22.2022.abstract AB 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.