脊髓小脑共济失调3型（SCA3/MJD）是最常见的脊髓小脑共济失调亚型，其发病机制未明确，临床上缺乏有效治疗。研究表明，SCA3中存在细胞内转运障碍，而参与神经元胞内运输的重要蛋白Hap1可能通过与ataxin-3的蛋白相互作用在SCA3发病机制中发挥重要作用。前期工作中，我们在体外水平进一步证实了ataxin-3与Hap1存在蛋白相互作用。本课题拟在细胞、小鼠和SCA3患者脑组织水平进一步证实ataxin-3蛋白与Hap1蛋白的相互作用，并确定蛋白的相互作用结构域，在体内及体外水平探讨ATXN基因突变对蛋白相互作用的影响，明确突变型ataxin-3蛋白对Hap1介导的细胞内转运的的影响，进一步探讨野生型和突变型ataxin-3蛋白是否影响Hap1蛋白磷酸化或Hap1蛋白与其他动力分子的结合，从而探寻Hap1介导的细胞内转运在SCA3发病机制中的作用，为寻找SCA3治疗靶点提供新的思路。

Spinocerebellar ataxia type 3, also called Machado-Joseph disease (SCA3/MJD), is the most common subtype of spinocerebellar ataxias. SCA3/MJD is one of the nine polyglutamine diseases. There is lack of effective therapy for the disease, as the pathogenesis of SCA3/MJD remains unclear. Recent studies indicated that intracellular transport defect may contribute to degeneration of nerve cells in SCA3/MJD. And huntingtin-associated protein 1 (Hap1), which involves in intracellular transportation in neurons, may play an important role in the pathogenesis of SCA3/MJD through its interaction with ataxin-3. Using immunofluorescent double labeling, we found an co-localization of ataxin-3 and Hap1 in cytoplasm punctual, which suggest the binding between ataxin-3 and Hap1 in vitro. Further, we plan to investigate the ataxin-3 and Hap1 interaction both in vitro and in vivo, and to identify the region of Hap1 crucial for interaction with ataxin-3. We also plan to investigate whether mutant ataxin-3 affects its binding with Hap1, and to clarify whether mutant ataxin-3 affects Hap1-mediated intracellular transport and the possible mechanisms underlie. This research may bring new insight in searching for therapeutic target of SCA3/MJD.