Fumio Nakamura
Department School of Medicine, School of Medicine Position Professor and Division head |
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Article types | Original article |
Language | English |
Peer review | Peer reviewed |
Title | Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice. |
Journal | Formal name:eNeuro Abbreviation:eNeuro ISSN code:23732822/23732822 |
Domestic / Foregin | Foregin |
Volume, Issue, Page | 9(3),pp.0133-22 |
Author and coauthor | 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 |
Publication date | 2022/05/23 |
Summary | 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. |
DOI | 10.1523/ENEURO.0133-22.2022 |
PMID | 35523582 |