帕金森病（PD）是一种常见的神经退行性疾病，其中线粒体损伤被认为是导致其病理改变的核心因素其之一。最近国内外研究表明parkin介导的线粒体自噬参与了细胞保护。由于parkin是一个E3链接酶，发现其作用的线粒体底物对线粒体自噬至关重要。我们的前期结果显示parkin可与线粒体蛋白Nix结合，Nix可能介导了parkin的线粒体自噬。本课题拟在前期预实验基础上，运用生化、细胞学技术，在细胞和动物模型上研究（1）Parkin是否泛素化Nix以及参与线粒体自噬的细胞生物学分子机制；（2）环境因素鱼藤酮等药物对parkin和Nix的影响；（3）动物模型中parkin和Nix对损伤线粒体清除，以及对中脑多巴胺能神经元保护作用。通过上述研究，阐述parkin的关键底物对线粒体清除所起的作用及其机制，并探讨其在体保护作用。

Parkinson's disease is a common neurodegenerative disease. One of the core factors that results in PD pathogenesis is the damage of mitochondria. Recent studies showed that parkin-mediated mitophagy is involved in the cellular protection. As parkin is an E3 ligase, it is important to identify its mitochondrial substarte that is involved in mitophagy. We recently found that parkin interacts with the mitochondrial protein Nix and that Nix may be involved in perkin-mdiated mitophagy. Based on these findings, we plan to investigate following issues: (1)if parkin ubiquitinates Nix and what is the mechanism for mitophagy; (2)the impact of drugs such as rotenone on parkin and Nix; (3)mitophagy for damaged mitochondria driven by parkin/Nix and its protective effects in animal models. We expect to elucidate by which mechanism parkin functions in mitophagy by regulating its substrate and explore its role in neuroprotection in vivo.