HIF-1α-ATP13A2信号通路对帕金森病多巴胺能神经元损伤的保护作用和机制研究

帕金森病相关基因ATP13A2失功能突变可致溶酶体功能障碍及α-共核蛋白聚集，其启动子区域存在缺氧反应原件(HRE)，低氧或过表达HIF-1α可增加其活性。我们在MPP+造模中发现，MPP+作用时间延长能增加HIF-1αmRNA及蛋白水平，但未减少细胞凋亡；Orexin-A通过诱导HIF-1α对多巴胺能神经元起保护作用；HRE核心序列存在CpG岛，推测MPP+导致HRE核心序列甲基化阻碍了HIF-1α与HRE的结合而抑制了ATP13A2 的转录活性，Orexin-A的神经保护作用可能与其对该位点去甲基化及上调HIF-1α有关。OrexinA可能调控HIF-1α-ATP13A2信号通路保护多巴胺能神经元损伤，上调ATP13A2表达可能成为帕金森病治疗新靶点。本课题拟探讨Orexin-A对ATP13A2启动子活性和HIF-1α-ATP13A2通路的表达调控机制，阐明其对帕金森病的神经保护作用。

As one of the newly discovered gene related to Parkinson’s disease, the loss-of-function mutations of ATP13A2 could result in lysosomal dysfunction and the subsequent accumulation of alpha-synuclein, Enhanced expression of ATP13A2 can reverse the effects. In addition, the promoter of ATP13A2 contains HRE regulatory elements, hypoxia or over-expression of HIF-1 can significantly increase the levels of ATP13A2. In our previous study, we found that MPP+ can increase the mRNA and protein level of HIF-1α but the changes did not rescue the apoptosis of SH-SY5Y cells. And also, our previous studies have demonstrated that Orexin-A have the neuroprotection effects on MPP+ induced dopaminergic neuronal injury by inducting the expression of HIF-1α. On the basis of the core sequence of HRE which contains CpG island, we speculated that MPP+ has an additional effect on the methylation of the HRE element of ATP13A2 promoter which prevented the link with HIF-1α and the protective effects of Orexin-A was associated with the demethylation and the enhanced level of HIF-1α. Therefore, we hypothesized that HIF-1α-ATP13A2 pathway might play an important role in the neuroprotection of dopaminergic neuronal damage in PD, and up-regulating the expression of ATP13A2 might provide a novel therapeutic target for the treatment of PD. Our project would set up PD model in vivo and in vitro, explore the effect of Orexin-A on the promoter activity of ATP13A2 and its role in the HIF-1α-ATP13A2 pathway, and further evaluate the possibility of up-regulation of ATP13A2 in the neuroprotective treatment in PD, our study would be of great clinical significance.