TET2在帕金森病多巴胺能神经元损伤中的作用机制及调控研究

帕金森病（PD）中脑多巴胺能神经元的损伤机制一直是人们的研究重点。TET2作为神经系统表达丰富的羟甲基化酶，是生理情况下羟甲基化过程中非常重要的组成成分。迄今为止，对TET2与PD的关系仍知之甚少。我们的预实验结果提示，TET2在PD发病机制中可能起重要作用，并且受到去乙酰化酶SIRT1的调控，但其作用机制有待进一步探讨。为此，我们提出假说：TET2-CDKN2A-P-Rb/p53通路可能通过诱导细胞衰老及凋亡通路导致PD的发生，并且上调SIRT1的表达可通过抑制SIRT1-TET2通路调控DNA羟甲基化，实现其对多巴胺能神经元的保护作用。本研究拟从分子、细胞及动物整体水平等多方面探讨TET2在PD发病机制及SIRT1神经保护作用中扮演的角色，明确TET2通过诱导细胞凋亡对多巴胺能神经元的损伤机制及调控，为PD的预防及治疗提供新的思路。

The mechanism of dopaminergic neuronal injury in Parkinson's disease (PD) has been the focus of researchers. As a nervous system expressing rich methylolase, TET2 is a very important component in the physiological methylolation process. However, little is known about the relationship between TET2 and PD. Our preliminary results suggest that TET2 may play an important role in the pathogenesis of PD and it could be regulated by the deacetylase SIRT1, but its mechanism needs to be further explored. To this end, we hypothesized that the TET2-CDKN2A-P-Rb/p53 pathway may lead to the development of PD by inducing cellular senescence and apoptotic pathways, and up-regulating the expression of SIRT1 may regulate DNA methylolation by inhibiting the SIRT1-TET2 pathway to achieve its protective effect on dopaminergic neurons. The aim of our study is to investigate the role of TET2 in the pathogenesis of PD and the neuroprotective effect of SIRT1 from the aspects of molecular, cellular and animal levels, and to clarify the mechanism and regulation of TET2 in dopaminergic neurons by inducing apoptosis. Our research may provide new ideas for the prevention and treatment of PD.