铜锌过氧化物歧化酶Cu/Zn-superoxide dismutase（SOD1）基因突变会导致其编码产物在病人体内发生聚集，并引发肌萎缩性脊髓侧索硬化症（ALS）。同时SOD1病理突变体对线粒体有毒性作用，此毒性导致的线粒体功能紊乱被认为是ALS的核心发病机制之一，但是SOD如何导致线粒体损伤的作用机制尚不十分明确。本课题根据我们最近发现的去泛素化酶ataxin-3调控突变SOD1聚集以及ataxin-3与线粒体的重要功能蛋白Bcl-XL结合为出发点，拟在细胞和动物模型上深入研究ataxin-3作为中介调控SOD1聚集与Bcl-XL相互作用的分子机制，运用分子生物学和细胞生物学等手段，明确ataxin-3对于SOD1聚集引起的线粒体功能损伤的调控作用，并探索此作用在ALS发生发展中的意义。本研究将有助于进一步在分子水平了解ALS的核心发病机理，为ALS的治疗提供新的思路。

Mutation in Cu/Zn-superoxide dismutase (SOD1) gene and is associated with aggregation of SOD1 protein and can cause Amyotrophic lateral sclerosis (ALS). Studies have shown that mitochondria dysfunction is the key mechanism underlying ALS and mutant SOD1 is toxic to mitochondria. However, how could mutant SOD1 impair mitochondria is still not clear. In our experiment we found the deubiquitinating enzyme ataxin-3 could target to mutant SOD1 aggregates and mitochondrial protein Bcl-XL together. In this study we will use cultured cells and transgenic animal models, along with a variety of molecular and cellular biology to further investigate the mechnism of ataxin-3-mediated SOD1-Bcl-XL association and explore the role of this regulation in SOD1 aggregate-induced mitochondria dysfunction and in ALS pathogenesis. This study will be helpful for the further understanding of basic molecular mechnism underlying ALS, and could possibly lead to strategy for the effective treatment of ALS.