title: Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway.
abstract: 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.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: liuft110@aliyun.com.
authors.forename: Feng-Tao
authors.initials: FT
authors.lastname: Liu
authors.affiliation: 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. Electronic address: yujieyang1015@me.com.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: jungliw@126.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: shanli1121@163.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: tangyilin10@163.com.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Tang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: orangerange_zj@hotmail.com.
authors.forename: Jue
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: besuretowin@gmail.com.
authors.forename: Zhen-Yang
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: bgxiao@shmu.edu.cn.
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Xiao
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: jzuo@shmu.edu.cn.
authors.forename: Ji
authors.initials: J
authors.lastname: Zuo
authors.affiliation: Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: liuwen@shmu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China. Electronic address: wangjian336@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000071186:Beclin-1; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051844:alpha-Synuclein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D048055:Mitogen-Activated Protein Kinase 8; C049347:fasudil
keywords: A53T α-synuclein; Fasudil; Macroautophagy; Rho kinase