VPS35基因突变激活线粒体未折叠蛋白反应调节多巴胺能神经元活性的机制研究

VPS35作为一个与中老年人帕金森病(Parkinson’s Disease,PD)发病相关的隐性遗传基因备受关注。我们既往报道VPS35 D620N突变可导致多巴胺能神经元线粒体形态和功能损害，但在携带该突变的幼龄小鼠与老龄小鼠相比，脑黑质区多巴胺能神经元线粒体并无损害，动物行为亦无异常。进一步研究提示VPS35 D620N突变造成线粒体损伤同时也可激活线粒体未折叠蛋白反应(UPR)，从而修复突变导致的线粒体缺陷。为深入探讨VPS35突变激活UPR的具体机制，本研究应用定量蛋白质组学方法筛选并验证参与UPR激活的线粒体相关信号通路蛋白；描绘不同月龄转基因小鼠黑质多巴胺能神经元的目标信号通路蛋白、UPR、线粒体形态和功能的动态变化；并对不同月龄VPS35转基因小鼠的目标信号通路蛋白进行相应干预，观察多巴胺能神经元活性及动物行为变化。本项目将为PD病因治疗新干预靶点选择提供有价值的新线索。

VPS35 is getting more and more attention considered as a recessively inherited gene associated with late onset of Parkinson's disease (PD) in the old population. We have previously reported that VPS35 D620N mutations can cause morphological and functional impairment of mitochondria in dopaminergic neurons. However, comparing old transgenic mice to the younger ones, mitochondria of dopaminergic neurons in substantia nigra showed no impairment in young mice. Also, there is no abnormality in animal behavior. Further research indicated that VPS35 D620N mutation caused mitochondrial damage while simultaneously activated the mitochondrial unfolded protein response (UPR) to repair mitochondrial impairment. This study is aimed to explore the exactly mechanism of VPS35 mutation-activated UPR. Quantitative proteomics will be performed to screen and verify possible mitochondrial signaling protein involved in UPR activation, which could describe the dynamic changes in signaling pathways, UPR, morphology and function of mitochondria in mice with different ages. Furthermore, we try to intervene with targeted the signaling pathway in VPS35 transgenic mice at different ages to observe dopaminergic neuron activity and animal behavior changes. This study will provide a valuable clue to the selection of new targets for PD treatment.