亨廷顿病(HD)是一种单基因突变引起的神经退行性疾病，线粒体功能障碍是HD的病理特征之一，但其详细分子机制目前尚不清楚。亨廷顿蛋白突变体（mtHtt）抑制热休克转录因子1（HSF1）的活性，促进其降解，破坏蛋白质稳态平衡，导致神经细胞死亡。申请人前期结果发现HSF1在应激及HD模型中转位至线粒体，引发线粒体功能障碍与神经细胞凋亡。线粒体动力相关蛋白1（Drp1）在调控HSF1线粒体转位过程中发挥了重要作用。本项目拟利用蛋白质组学、RNA组学的方法解析HSF1调控线粒体功能的分子机制；通过腺相关病毒表达靶向线粒体HSF1研究其在HD病理过程中的关键作用。此外，拟设计小分子多肽干扰HSF1线粒体转位，探讨其能否挽救mtHtt介导的线粒体损伤；阐明其能否改善HD转基因小鼠病理学特征及行为学异常。通过上述研究，加深对HD模型中线粒体功能障碍分子机制的认识，为临床上治疗HD提供理论与实验基础。

Huntington's disease (HD) is a neurodegenerative disease caused by single-gene mutations. Mitochondrial dysfunction is one of the pathological features of HD, but its detailed molecular mechanism is still unclear. Mutant huntingtin (mtHtt) inhibits the activity of heat shock transcription factor 1 (HSF1), promotes its proteasome-mediated degradation and causes neuronal cell. Our previous results showed that HSF1 accumulates on the mitochondria under heat shock and HD pathological condition, which in turn leads to mitochondrial dysfunction and apoptosis. Dynamin-related protein 1 (Drp1) plays an important role in HSF1 translocation to the mitochondria. Proteomics analysis and RNA-seq analysis will be performed to profile the molecular mechanism of HSF1 in regulation of mitochondrial function. The contribution of mitochondria-accumulated HSF1 in the pathogenesis of HD will be determined by AAV mediated HSF1 expression. In addition, we will design a small peptide inhibitor that blocks HSF1 translocation to the mitochondria. Last, we will test whether the small peptide has a protective effect on the mutant huntingtin-induced mitochondrial dysfunction, and improves pathological features and behavioral abnormalities in YAC128 mice. Our research will provide a novel molecular mechanism of mitochondrial dysfunction in Huntington's disease and a new therapeutic target to treat Huntington's disease.