JNK3的小肽抑制剂通过抑制ASK1-JNK3信号通路保护多巴胺能神经元免受MPTP诱导的损伤。
Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway.
作者信息
Pan Jing, Li Hui, Zhang Bei, Xiong Ran, Zhang Yu, Kang Wen-Yan, Chen Wei, Zhao Zong-Bo, Chen Sheng-Di
机构信息
Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Stem Cell Biology & Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes of Biological Sciences (SIBS), Chinese Academy of Science (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
PLoS One. 2015 Apr 9;10(4):e0119204. doi: 10.1371/journal.pone.0119204. eCollection 2015.
INTRODUCTION AND AIMS
The ASK1-JNK3 signaling pathway plays a pivotal role in the pathogenesis of Parkinson's disease (PD). The specific binding of β-arrestin2 to JNK3 is essential for activation of the ASK1-JNK3 cascade, representing a potential therapeutic target for preventing dopaminergic neuronal death in PD. The aim of this study was to identify a novel strategy for the prevention of dopaminergic neuronal death in PD.
METHODS
Based on the specific binding of β-arrestin2 to JNK3, a 21-amino-acid fusion peptide, termed JNK3-N-Tat, was synthesized. We evaluated the ability of this peptide to inhibit the binding of β-arrestin2 to its target domain in JNK3 in vitro and in vivo.
RESULTS
The JNK3-N-Tat peptide inhibited activation of the ASK1-JNK3 cascade by disrupting the interaction between β-arrestin2 and JNK3. JNK3-N-Tat exerted beneficial effects through pathways downstream of JNK3 and improved mitochondrial function, resulting in attenuated MPP+/MPTP-induced damage. JNK3-N-Tat protected mesencephalic dopaminergic neurons against MPTP-induced toxicity.
CONCLUSIONS
JNK3-N-Tat, a JNK3-inhibitory peptide, protects dopaminergic neurons against MPP+/MPTP-induced injury by inhibiting the ASK1-JNK3 signaling pathway.
引言与目的
ASK1-JNK3信号通路在帕金森病（PD）的发病机制中起关键作用。β-抑制蛋白2与JNK3的特异性结合对于激活ASK1-JNK3级联反应至关重要，这代表了一种预防PD中多巴胺能神经元死亡的潜在治疗靶点。本研究的目的是确定一种预防PD中多巴胺能神经元死亡的新策略。
方法
基于β-抑制蛋白2与JNK3的特异性结合，合成了一种名为JNK3-N-Tat的21个氨基酸的融合肽。我们在体外和体内评估了该肽抑制β-抑制蛋白2与其在JNK3中的靶结构域结合的能力。
结果
JNK3-N-Tat肽通过破坏β-抑制蛋白2与JNK3之间的相互作用抑制ASK1-JNK3级联反应的激活。JNK3-N-Tat通过JNK3下游通路发挥有益作用并改善线粒体功能，从而减轻MPP+/MPTP诱导的损伤。JNK3-N-Tat保护中脑多巴胺能神经元免受MPTP诱导的毒性。
结论
JNK3-N-Tat，一种JNK3抑制肽，通过抑制ASK1-JNK3信号通路保护多巴胺能神经元免受MPP+/MPTP诱导的损伤。
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