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 Asano, Tetsuya A1 Nakamura, Haruko A1 Kawamoto, Yuko A1 Tada, Mikiko A1 Kimura, Yayoi A1 Takano, Hiroshi A1 Yao, Ryoji A1 Saito, Hiroya A1 Ikeda, Takuya A1 Komiya, Hiroyasu A1 Kubota, Shun A1 Hashiguchi, Shunta A1 Takahashi, Keita A1 Kunii, Misako A1 Tanaka, Kenichi A1 Goshima, Yoshio A1 Nakamura, Fumio A1 Takeuchi, Hideyuki A1 Doi, Hiroshi A1 Tanaka, Fumiaki 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.