利福平调控α-Synuclein的SUMO化对多巴胺能神经元的保护作用及机制

Abnormal accumulation of α-Syn is an important reason of the dopaminergic neuron apoptosis in PD. Lots of studies have shown that promoting SUMOylation of α-Syn can prevent it from abnormal accumulation. We have reported that rifampicin exhibited neuroprotective effects in PD models by inhibiting abnormal accumulation of α-Syn, but the mechanisms have not been fully elucidated. Recently, we found that,α-Syn-SUMOylation was obviously increased after pretreatment of rifampicin in rotenone-induced PC12 cells. In addition, abnormal accumulation of α-Syn was augmented when SUMO1 was down-regulated, and neuroprotective effects of rifampicin on PC12 cells was diminished. Therefore, we proposed that rifampicin played a role in dopaminergic neuroprotection by regulating α-Syn SUMOylation, which could inhibit abnormal accumulation of α-Syn. Our project adopts the rotenone-induced PD cell and rat model, to identify the effect of rifampicin on the expression of SUMO（1/2/3）, to investigate the specific SUMO enzymes (E1 / E2 / E3) which are regulated by rifampicin, and whether the inhibitive effect of rifampicin on α-Syn accumulation is mediated by α-Syn SUMOylation in cell protection. This research aims to clarify the new neuroprotective mechanism of rifampicin and offer new drug targets for PD treatment.

α突触核蛋白（α-Syn）异常聚集是导致帕金森病（PD）多巴胺能神经元凋亡的核心环节。研究表明：促进SUMO化可抑制α-Syn的异常聚集。我们已报道利福平通过抑制α-Syn异常聚集对PD模型起保护作用，但机制未明。最近又发现：在鱼藤酮诱导的PD模型中，利福平预处理后SUMO化的α-Syn明显增多；下调SUMO1后，利福平对α-Syn异常聚集的抑制作用减弱，且对细胞的保护作用降低。故我们推测：利福平通过调控α-Syn的SUMO化，抑制其异常聚集而保护多巴胺能神经元。本项目采用鱼藤酮诱导PD细胞和大鼠模型，研究利福平对SUMO蛋白（1/2/3）表达的影响；阐明利福平调控的具体SUMO化酶(E1/E2/E3)；探讨利福平是否下调去SUMO化酶（SENP1/3)，明确SUMO化在利福平抑制α-Syn异常聚集保护多巴胺能神经元中的作用，旨在阐明利福平发挥神经保护作用的新机制，为PD治疗提供新靶点。

α突触核蛋白（α-Syn）异常聚集是导致帕金森病（PD）多巴胺能神经元凋亡的核心环节。研究表明：促进SUMO化可抑制α-Syn的异常聚集。我们已报道利福平通过抑制α-Syn异常聚集对PD模型起保护作用，但机制未明。最近又发现：在鱼藤酮诱导的PD模型中，利福平预处理后SUMO化的α-Syn明显增多；下调SUMO1后，利福平对α-Syn异常聚集的抑制作用减弱，且对细胞的保护作用降低。故我们推测：利福平通过调控α-Syn的SUMO化，抑制其异常聚集而保护多巴胺能神经元。本项目采用鱼藤酮诱导PD细胞和大鼠模型，我们发现利福平通过提高α-Syn的SUMO化水平起到抵御鱼藤酮对PC12细胞的毒性作用，阐明了利福平发挥神经保护作用的新机制，为PD治疗提供新靶点。