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.