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.