Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice
Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice
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DOI：
10.1523/eneuro.0133-22.2022
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发表时间：
2022-05-01
期刊：
影响因子：
3.4
通讯作者：
Tanaka, Fumiaki
中科院分区：
文献类型：
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作者：
Asano, Tetsuya;Nakamura, Haruko;Tanaka, Fumiaki
肌萎缩性侧索硬化症（ALS）是一种快速进展和致命的神经退行性疾病，影响上、下运动神经元；然而，其病理机制尚未完全阐明。利用全面的磷酸化蛋白质组学方法，我们发现过度表达人类超氧化物歧化酶突变体SOD1(G93)(a)的ALS模型小鼠腰椎脊髓中522丝氨酸处的Collapsin反应介质蛋白1（Crmp1）磷酸化升高。我们分别使用S522磷酸化位点缺失的Crmp1(S522A) （Ser522 -> Ala）敲入（Crmp1(ki/ki)）小鼠和Crmp1敲除（Crmp1(-/-)）小鼠，研究了Crmp1磷酸化和缺失对SOD1（G93A）小鼠的影响。与SOD1（G93A）相比，Crmp1(ki/ki)/SOD1（G93A）小鼠在轮轮试验中表现出较长的跌倒潜伏期，而Crmp1(-/-)/SOD1（G93A）小鼠表现出较短的跌倒潜伏期。Crmp1(ki/ki)/SOD1（G93A）小鼠的存活时间延长，而Crmp1(-/-)/SOD1（G93A）小鼠的存活时间没有延长。与这些表型发现一致，Crmp1(ki/ki)/SOD1（G93A）小鼠中残留的运动神经元和神经支配的神经肌肉连接（NMJs）相对保存较好，而不影响小胶质细胞和星形胶质细胞病理。蛋白质组改变的通路分析显示sirtuin信号通路在Crmp1(ki/ki)/SOD1（G93A）和Crmp1(-/)(-)/SOD1（G93A）小鼠中具有相反的作用。我们的研究表明，修饰CRMP1磷酸化是一种潜在的治疗ALS的策略。
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(G93)(A)). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1(G93A) mice using Crmp1(S522A) (Ser522 -> Ala) knock-in (Crmp1(ki/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.