去乙酰化酶Sirtuins家族是一条与衰老的过程密切相关的通路。前期关于线粒体中的SIRT3在神经退行性疾病中的报道较少，尤其在亨廷顿疾病中的功能还不清楚。我们的初步数据提示SIRT3去乙酰化亚甲基四氢叶酸脱氢酶2（MTHFD2），调控MTHFD2的蛋白稳定性，从而影响产物NADPH的水平来调节reactive oxygen species(ROS)和下游的s-adenosylmethionine (SAM)的浓度，进而影响细胞的超氧水平和表观遗传稳态。本研究计划聚焦于人脑衰老向退行性变化演变的早期过程，探索在亨廷顿疾病中的SIRT3调控MTHFD2来影响线粒体功能的作用机制，揭示线粒体应对超氧应激和DNA甲基化在分子水平和组织细胞水平的变化特征，阐述SIRT3在人脑向退行性变化演变的调控机制。本研究不仅加强对衰老相关疾病发生的认识，还进一步为靶向SIRT3来治疗亨廷顿疾病提供新的策略。

The NAD+-dependent deacetylase Sirtuins family have emerged as critical regulators for aging and longevity in multiple model organisms. An amount of previous studies have investigated the function of SIRT1 and SIRT2 in neurodegerative diseases, but the major mitochondrial deacetylase SIRT3 has fewer reports about neurodegerative diseases, especially the function of SIRT3 in Huntington’s disease is unclear. Our preliminary data indicate that SIRT3 may deacetylate mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and regulate its protein stability, therefore affecting the levels of NADPH and s-adenosylmethionine, which resulting to balance cellular oxidative status and epigenetic homeostasis. In this study we focus on the early degenerative processes during human brain senescence and will illuminate the mechanism of SIRT3 regulation MTHFD2 and mitochondrial functions in Huntington disease. The biological function of mitochondrial response to superoxidative stress and DNA methylation changes in molecule level and tissue level will be determined. We will characterize SIRT3 function in the degenerative processes of brain. This study will not only strengthen our knowledge of aging-related neurodegerative diseases, but also provides a new strategy for targeting SIRT3 to treat Huntington’s disease.