Togashi Kentaro, Hasegawa Masaya, Nagai Jun, Tonouchi Aine, Masukawa Daiki, Hensley Kenneth, Goshima Yoshio, Ohshima Toshio
Department of Life Science and Medical Bio-Science, Waseda University, Tokyo, Japan.
Japan Society for the Promotion of Science, Tokyo, Japan.
Genes Cells. 2019 Jan;24(1):31-40. doi: 10.1111/gtc.12651. Epub 2018 Nov 18.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by slow and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Levodopa (l-Dopa), the current main treatment for PD, supplies dopamine, but it does not prevent neurodegeneration. There is thus no promising remedy for PD. Recent in vitro study showed the increase in the phosphorylation levels of Collapsin Response Mediator Protein 2 (CRMP2) is involved in dopaminergic axon degeneration. In the present study, we report elevation of CRMP2 phosphorylation in dopaminergic neurons in SNc after challenge with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a common model for PD. Genetic suppression of CRMP2 phosphorylation by mutation of the obligatory Cyclin-dependent kinase 5 (Cdk5)-targeted serine-522 site prevented axonal degradation in the nigrostriatal pathway of transgenic mice. As a result, the degree of MPTP-induced motor impairment in the rotarod test was suppressed. These results suggest that suppression of CRMP2 phosphorylation may be a novel therapeutic target for PD.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质致密部（SNc）中多巴胺能神经元缓慢且进行性退化。左旋多巴（l-Dopa）是目前治疗PD的主要药物，它能提供多巴胺，但不能阻止神经退行性变。因此，目前尚无治疗PD的有效方法。最近的体外研究表明，塌陷反应介导蛋白2（CRMP2）磷酸化水平的升高与多巴胺能轴突退化有关。在本研究中，我们报告了在用多巴胺能神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）攻击后，SNc中多巴胺能神经元的CRMP2磷酸化水平升高，MPTP是一种常见的PD模型。通过必需的细胞周期蛋白依赖性激酶5（Cdk5）靶向的丝氨酸-522位点突变对CRMP2磷酸化进行基因抑制，可防止转基因小鼠黑质纹状体通路中的轴突退化。结果，在转棒试验中，MPTP诱导的运动障碍程度得到抑制。这些结果表明，抑制CRMP2磷酸化可能是治疗PD的一个新的治疗靶点。
