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

• Published in: eNeuro Vol. 9; no. 3; p. ENEURO.0133-22.2022
• Main Authors: Asano, Tetsuya, Nakamura, Haruko, Kawamoto, Yuko, Tada, Mikiko, Kimura, Yayoi, Takano, Hiroshi, Yao, Ryoji, Saito, Hiroya, Ikeda, Takuya, Komiya, Hiroyasu, Kubota, Shun, Hashiguchi, Shunta, Takahashi, Keita, Kunii, Misako, Tanaka, Kenichi, Goshima, Yoshio, Nakamura, Fumio, Takeuchi, Hideyuki, Doi, Hiroshi, Tanaka, Fumiaki
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 01.05.2022
• Subjects: New Research; ALS; CRMP1; SOD1
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0133-22.2022

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 in mice using Crmp1 (Ser522→Ala) knock-in ( ) mice in which the S522 phosphorylation site was abolished and knock-out ( ) mice, respectively. / mice showed longer latency to fall in a rotarod test while / mice showed shorter latency compared with mice. 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.