DA神经元α-syn蛋白积聚诱发的ER应激与HtrA2/Nurr1分子调控紊乱的的机制研究

α-synuclein在DA神经元内积聚是帕金森病的病理学标志，多种分子参与DA神经元的内质网（ER）应激。我们发现：①Nurr1是DA神经元抗凋亡的关键基因，其缺损增加神经元对毒素的敏感性。②6-OHDA损伤DA神经元的HtrA2功能，使α-syn蛋白积聚，诱发ER应激，阻止Wnt信号的细胞内传导，GSK3β活性升高，导致DA神经元变性。但我们对α-syn、HtrA2、Nurr1及Wnt/GSK3β等分子在细胞凋亡过程中的作用及其相互之间的调控关系并不完全清楚。本项目以人HtrA2、Nurr1缺陷iPS细胞和HtrA2-/-小鼠、Nurr1+/-杂合鼠等为基础，通过毒素干预和基因沉默等方法，分析不同条件下，模型细胞内α-syn积聚/细胞变性介导的ER应激的分子途径，检测上述信号分子的相互调控关系，从而揭示重要分子参与DA神经元凋亡的ER应激的分子机制及关键靶点的神经保护作用。

Aberrant α-synuclein aggregation in Dapamnergic Neuron (DAergic neuron) is a pathological marker of Parkinson's disease.Much molecular including Nurr1 and HtrA2 may participate in the process of Dopaminergic cell appotosis through endoplasmic reticulum stress (ER) in DAergic cells. We found: ①6-OHDA resulted in HtrA2 dysfunction, mediated α-synuclein aggregation related ER stress in DAergic neuron. The α-synuclein aggregation blocked Wnt signal pathway and resulted in degeneration of DAergic neuron. ② Nurr1 plays key role in DAergic cell's development, survival and its functional maintain and Nurr1 defection results in DAergic dysfunction of Neurons impacted by environment toxin. However, the molecular mechanism and their interaction relationship among the genes such as HtrA2,α-synuclein and Nurr1 in Parkinson disease is still far from clear. In this project, using PD cell and animal models such as HtrA2，Nurr1+/- iPS cell and HtrA2-/-mice as well as Nurr1+/- mice, we plan to analyze the association of Wnt/GSK3β pathway with α-synuclein aggregation mediated by ER stress from HtrA2 dysfunction and Nurr1 deficiency, and detect the molecule interaction between α-synuclein, HtrA2 andNurr1. We hope to deeply underst the process of Dopaminergic cell appotosis and the mechanism of Wnt/GSK3β pathway mediated by ER stress from HtrA2 and Nurr1 in DAergic neuron and assess their neural protection by these target molecules.