1. Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice
- Author
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Tetsuya Asano, Haruko Nakamura, Yuko Kawamoto, Mikiko Tada, Yayoi Kimura, Hiroshi Takano, Ryoji Yao, Hiroya Saito, Takuya Ikeda, Hiroyasu Komiya, Shun Kubota, Shunta Hashiguchi, Keita Takahashi, Misako Kunii, Kenichi Tanaka, Yoshio Goshima, Fumio Nakamura, Hideyuki Takeuchi, Hiroshi Doi, and Fumiaki Tanaka
- Subjects
Disease Models, Animal ,Mice ,Superoxide Dismutase-1 ,Superoxide Dismutase ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Animals ,Mice, Transgenic ,General Medicine ,Phosphorylation - 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 (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion inSOD1G93Amice using Crmp1S522A(Ser522→Ala) knock-in (Crmp1ki/ki) mice in which the S522 phosphorylation site was abolished andCrmp1knock-out (Crmp1−/−) mice, respectively.Crmp1ki/ki/SOD1G93Amice showed longer latency to fall in a rotarod test whileCrmp1−/−/SOD1G93Amice showed shorter latency compared withSOD1G93Amice. Survival was prolonged inCrmp1ki/ki/SOD1G93Amice but not inCrmp1−/−/SOD1G93Amice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved inCrmp1ki/ki/SOD1G93Amice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects inCrmp1ki/ki/SOD1G93AandCrmp1−/−/SOD1G93Amice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.
- Published
- 2022