利福平通过上调GRP78分子对多巴胺能神经元的保护作用及机制

Endoplasmic reticulum stress (ERS) contributes to apoptosis of dopaminergic neurons ,which plays an important role in the pathological process of Parkinson's disease (PD).We reported that rifampicin had neural protective effect in PD models, however, the mechanisms have not been fully elucidated . Recently, we found that GRP78 ,a protective molecule in ERS, was upregulated obviously in PC12 cells treated by rifampicin; Moreover, rifampicin could inhibit the expression of rotenone-induced endoplasmic reticulum-specific apoptosis molecule Caspase12; While knocking down GRP78 attenuated the inhibition of Caspase12 of rifampicin. Therefore , we proposed that rifampicin could suppress rotenone induced ERS-related apoptosis via upregulation of GRP78. In this project, we will develop rotenone-induced cellular and animal models of PD, to study whether rifampicin can affect the expression of GRP78; to clarify whether rifampicin can inhibit CHOP, ASK1/JNK and Caspase12 ERS related apoptosis pathways; to figure out what is the role of GRP78 in the signal pathways that mentioned above; finally, to identify how rifampicin selectively regulate upstream signaling pathways of GRP78. The purpose of this project is not only to elucidate new mechanisms involved in neuroprotective effect of rifampin, but also to offer new drug target for PD treatment.

内质网应激（ERS）所致的黑质多巴胺能细胞凋亡是帕金森病（PD）的重要发病机制。我们已报道利福平通过抑制凋亡对PD细胞和动物模型起神经保护作用，但机制尚未完全阐明。最近我们发现：利福平既可上调PC12细胞内保护性分子葡萄糖调节蛋白（GRP78），又可抑制鱼藤酮诱导的内质网特异性凋亡分子Caspase12的表达，下调GRP78使利福平抑制Caspase12激活的作用消失。故我们推测：利福平通过上调多巴胺能神经元GRP78的表达而抑制鱼藤酮诱导的ERS相关性凋亡。本项目用鱼藤酮诱导的PD细胞和大鼠模型，研究利福平对GRP78表达的影响；阐明利福平能否抑制CHOP、ASK1/JNK、Caspase12等ERS相关性凋亡通路；明确GRP78分子在利福平抑制ERS相关性凋亡中的作用；探讨利福平调控GRP78的具体信号通路。本课题旨在阐明利福平发挥神经保护作用的新机制，为PD治疗提供新的药物靶点。

内质网应激（ERS）所致的黑质多巴胺能细胞凋亡是帕金森病（PD）的重要发病机制。我们已报道利福平通过抑制凋亡对 PD 细胞和动物模型起神经保护作用，但机制尚.未完全阐明。之前我们发现：利福平既可上调 PC12 细胞内保护性分子葡萄糖调节蛋白（GRP78），又可抑制鱼藤酮诱导的内质网特异性凋亡分子 Caspase12 的表达，下调 GRP78 使利福平抑制 Caspase12 激活的作用消失。故我们推测：利福平通过上调多巴胺能神经元 GRP78的表达而抑制鱼藤酮诱导的 ERS 相关性凋亡。本项目中，我们用鱼藤酮诱导的PD细胞和大鼠模型，发现利福平通过激活未折叠蛋白反应（UPR）中的PERK-eIF2α-ATF4凋亡通路上调GRP78分子，明确GRP78分子的上调通过抑制内质网特异性凋亡分子 Caspase12 的表达介导了利福平对鱼藤酮诱导的多巴胺能神经元的保护作用及机制，为探寻老药利福平防治帕金森病的新机制及新的药物靶点提供理论依据。