对家族性ALS/FTD直接相关蛋白复合体C9ORF72-SMCR8-WDR41结构和功能的研究

肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两类多发于中老年人群的神经退行性疾病，目前尚无有效的治疗方法。C9ORF72是与大部分家族性ALS/FTD直接相关的基因，但是该基因功能异常导致ALS/FTD的分子机理还不清晰。研究表明，C9ORF72编码的蛋白C9ORF72能够与SMCR8和WDR41形成复合体，但是C9ORF72-SMCR8-WDR41复合体(CSW复合体)的具体功能还不清楚，其功能异常导致蛋白聚集体产生，进而导致ALS/FTD的机制还有待探究。本研究拟利用细胞生物学、生物化学、结构生物学的方法，探究CSW复合体激活Rab的分子机制以及结构基础；探究CSW复合体发挥功能的共作用因子；探究CSW复合体调节自噬的分子机制；探究CSW复合体调控膜运输和自噬异常导致蛋白聚集体在细胞内积累的分子机制，为C9ORF72相关ALS/FTD的诊疗提供理论依据。

Both amyotrophic lateral sclerosis（ALS）and frontotemporal dementia (FTD) belong to neurodegenerative diseases, of which the peak age of onset is 50 to 60. There is no cure for both diseases by far. C9ORF72 was identified to be associated with familial ALS/FTD directly, however, of which the mechanistic basis is still elusive. Previous studies show that C9ORF72 can bind to SMCR8 and WDR41 to form a stable complex, of which the function awaits exploration. The mechanism that dysfunctions of the C9ORF72-SMCR8-WDR41 complex (CSW complex) lead to the accumulation of protein aggregations and familial ALS and FTD is yet unclear. In this study, taking advantage of cell biological, biochemical, and structure biological methods, we plan to explore the mechanistic and structural basis of how CSW complex activates Rabs and regulates autophagy, and study the molecular basis of how the dysfunctions in the regulation of membrane trafficking and autophagy by the C9ORF72-SMCR8-WDR41 complex leads to the accumulation of protein aggregations, which would facilitate the therapies of ALS/FTD.