NUS1基因变异对自噬-溶酶体通路的影响在帕金森病发病机制中作用的研究

帕金森病（PD）是一种常见的神经退行性疾病，目前其致病机制仍未完全明确。本课题组前期在中国PD人群中发现NUS1基因为PD的新易感基因，首次提出NUS1基因罕见变异增加PD患病风险，NUS1缺失的细胞模型存在自噬异常。本项目拟在前期研究基础上，利用已构建的NUS1缺失细胞模型及NUS1条件敲除小鼠模型，应用透射电镜、Western blot、免疫组化、免疫共沉淀、蛋白质谱等分子生物学方法，进行自噬通路相关蛋白检测，分别从自噬活化、自噬流状态以及溶酶体降解等角度明确NUS1调控自噬-溶酶体通路的分子机制，探讨其是否通过对自噬-溶酶体通路的调控影响α-syn的降解，深入探讨NUS1基因变异导致PD的致病机制。

Parkinson's disease (PD) is a common neurodegenerative disease, and its pathogenesis is still unclear. Previously, our team found that NUS1 gene was a new susceptible gene for PD in Chinese PD population. This is the first time to identify the rare variants of NUS1 increase PD risk. We have found that there is autophagic flux inhibition exists in NUS1 null cell model. On the basis of previous studies, this project intends to culture NUS1 null cell model and breed NUS1 conditional knockout mice model to measure the autophagic flux signaling by using transmission electron microscopy, Western blot, immunohistochemistry, immunoprecipitation and other molecular biological methods. To clarify the mechanism caused by NUS1 mutation, the aspects of autophagic activation, autophagic flow status and lysosome degradation which regulate autophagy-lysosome pathway, will be studied. Further research will also focus on whether NUS1 affects the degradation of a-syn by affecting autophagy-lysosome pathway.