| First Author | Asano T | Year | 2022 |
| Journal | eNeuro | Volume | 9 |
| Issue | 3 | PubMed ID | 35523582 |
| Mgi Jnum | J:326374 | Mgi Id | MGI:7283686 |
| Doi | 10.1523/ENEURO.0133-22.2022 | Citation | Asano T, et al. (2022) Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice. eNeuro 9(3):ENEURO.0133-22.2022 |
| abstractText | 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(G93A)). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1(G93A) mice using Crmp1(S522A) (Ser522-->Ala) knock-in (Crmp1(k) (i) (/ki) ) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out (Crmp1 (-/-)) mice, respectively. Crmp1(ki) (/) (ki) /SOD1(G93A) mice showed longer latency to fall in a rotarod test while Crmp1 (-/-)/SOD1(G93A) mice showed shorter latency compared with SOD1(G93A) mice. Survival was prolonged in Crmp1(ki) (/) (ki) /SOD1(G93A) mice but not in Crmp1 (-/-)/SOD1(G93A) mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in Crmp1(ki) (/) (ki) /SOD1(G93A) mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1(ki) (/) (ki) /SOD1(G93A) and Crmp1 (-/-)/SOD1(G93A) mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS. |
