Liu Feng-Tao, Yang Yu-Jie, Wu Jian-Jun, Li Shan, Tang Yi-Lin, Zhao Jue, Liu Zhen-Yang, Xiao Bao-Guo, Zuo Ji, Liu Wen, Wang Jian
Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China; Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Brain Res. 2016 Feb 1;1632:9-18. doi: 10.1016/j.brainres.2015.12.002. Epub 2015 Dec 10.
Accumulation of α-synuclein (α-syn) is pivotally implicated in the pathogenesis of Parkinson׳s disease (PD), and enhancing its clearance might be a promising strategy in PD treatment. It has recently been shown that Rho kinase (ROCK) activation is involved in many neurodegenerative diseases, and some ROCK inhibitors might promote the degradation of abnormal protein aggregates. However, it is not known if fasudil, the only ROCK inhibitor available in clinical setting, could promote the degradation of α-syn, and ameliorate the α-syn induced neurotoxicity. In this regard, we investigated the effect of fasudil on neurite injury caused by A53T α-syn overexpression and the implicated pathway it might mediate. In the current study, we found that under the condition of A53T α-syn overexpression, the neurite outgrowth decreased significantly with the increasing expression of ROCK2. Fasudil, the ROCK inhibitor, ameliorated such neurotoxicity and promoted the clearance of A53T α-syn. Its underlying mechanism was supported by that fasudil could increase the macroautophagy activation via JNK 1 and Bcl-2 phosphorylation and beclin 1/Vps34 complex formation. Taken together, fasudil might be able to provide a novel and promising strategy for PD treatment by enhancing α-syn clearance and activating the JNK 1/Bcl-2/beclin 1 pathway.
α-突触核蛋白（α-syn）的积累在帕金森病（PD）的发病机制中起着关键作用，增强其清除可能是PD治疗的一个有前景的策略。最近有研究表明，Rho激酶（ROCK）激活与许多神经退行性疾病有关，一些ROCK抑制剂可能促进异常蛋白聚集体的降解。然而，尚不清楚临床可用的唯一ROCK抑制剂法舒地尔是否能促进α-syn的降解，并改善α-syn诱导的神经毒性。在这方面，我们研究了法舒地尔对A53T α-syn过表达引起的神经突损伤的影响及其可能介导的相关途径。在本研究中，我们发现，在A53T α-syn过表达的条件下，随着ROCK2表达的增加，神经突生长显著减少。ROCK抑制剂法舒地尔改善了这种神经毒性，并促进了A53T α-syn的清除。其潜在机制是法舒地尔可通过JNK 1和Bcl-2磷酸化以及beclin 1/Vps34复合物形成增加自噬激活。综上所述，法舒地尔可能通过增强α-syn清除和激活JNK 1/Bcl-2/beclin 1途径为PD治疗提供一种新的有前景的策略。
