脊髓小脑性共济失调3型/马查多-约瑟夫病（SCA3/MJD）是一种高致死率和致残率的神经退行性疾病，其发病机制尚未阐明，缺乏有效治疗方法。我们前期研究发现在SCA3/MJD患者PBMCs中ATP产生呈下降趋势，mGluR1表达呈上升趋势。本研究拟扩大SCA3/MJD样本筛选并验证病例组与对照组能量代谢物水平、mGluR1通路分子表达水平，寻找可用于评估临床表型和疾病进展的生物标志物；并在SCA3/MJD患者UiPSCs分化的神经元和转基因小鼠模型中通过应用mGluR1拮抗剂/激动、siRNA沉默/过表达mGluR1及下游关键分子干预mGluR1的活性/表达，明确mGluR1通路在SCA3/MJD能量代谢障碍中的分子机制及治疗作用。本研究首次从mGluR1通路的角度，深入探讨SCA3/MJD能量代谢障碍发病机制，并为推动mGluR1成为该类疾病治疗靶点的临床转化提供新证据。

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a neurodegenerative disorder with clinical heterogeneity as well as high mortality and disability. To date, the pathogenesis has not been fully elucidated and has no effective therapy. We previously found lower ATP and higher mGluR1 levels in the peripheral blood mononuclear cells of SCA3/MJD patients. In this study, in a larger SCA3/MJD cohort, we intend to validate the different level of energy metabolites and the expression of mGluR1 pathway molecules, to explore the potential biomarkers as indication and valuation of the phenotype and disease progression, and to investigate the molecular mechanism of mGluR1 pathway in energy metabolism dysfunction in SCA3/MJD. In addition, we aimed to analyze the potential therapeutic effects of mGluR1 in the neurons derive from UiPSCs and in the mice model. The study will provide new clues to elucidate the pathogenesis and therapy prospect of SCA3/MJD.