变异亨廷顿蛋白下游基因通过抑制自吞噬参与神经衰老与退行的分子机制

以亨廷顿病为代表的polyQ疾病是研究神经衰老与退行的重要遗传学模型。申请人前期的工作中发现了一组亨廷顿病中表达异常并影响神经退行相关表型的基因: 亨廷顿病的致病蛋白，变异亨廷顿蛋白在衰老过程中导致这些基因表达上调或下调；而这些基因的表达异常被发现会抑制自吞噬，并参与神经退行。据大量文献报道，自吞噬的下降，会导致细胞中蛋白质量控制能力下降，是衰老及退行的重要特征和机制。因此，变异亨廷顿蛋白下游的这些基因的异常表达，可能通过抑制自吞噬，加速衰老，加重致病蛋白的积累和下游基因的表达异常，形成正反馈循环，最终导致神经退行。本项目将着重研究这些变异亨廷顿蛋白下游基因对自吞噬的作用及作用机制，并进一步揭示其是否通过调控自吞噬参与神经衰老与退行。本项目的实施将揭示衰老及衰老向退行演化的新基因及新分子机制，为衰老与退行相关疾病治疗提供线索和靶点，与指南目标高度吻合。

Huntington’s disease and other polyQ disorders provide well-established genetic models for studying ageing and neurodegeneration. Based on previous work, the applicant has revealed a group of dysregulated genes that influence neurodegeneration-relevant motor phenotypes in Huntington’s disease. As such, the disease-causing mutant HTT is upstream of these genes; perturbing the expression of these genes during ageing. The dysregulation of these genes has been found to inhibit autophagy and participate in neurodegeneration. Based on extensive literature, reduced autophagy is the key signature and cellular mechanism of ageing and neurodegeneration. Thus, the dysregulated genes down-stream of mHTT exacerbates ageing and accumulation of misfolded proteins potentially via their negative regulation of autophagy, and the dysregulation of these genes may be further aggravated, forming a positive feedback loop mechanism that eventually leads to neurodegeneration. In this project, we will study how these genes regulate autophagy, and as a consequence, influence ageing and neurodegeneration. This would reveal novel genes and molecular mechanisms through which ageing and neurodegeneration are regulated, providing new clues and potential drug targets for ageing and degeneration related diseases, in accordance with the National Strategic Research Plan.