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

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.

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。

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。项目负责人在本项目中揭示了导致亨廷顿病的致病蛋白mHTT的polyQ区域的构象多态性是疾病产生的源头，而下游激活的激酶MAPK11及HIPK3等对mHTT水平存在正反馈调控，促进了疾病发展过程中衰老向神经退行转化。项目负责人进一步提出并实现了通过驾驭自噬来特异性降解致病蛋白mHTT从而治疗疾病的药物研发新概念，自噬小体绑定化合物（Autophagosome Tethering Compounds，ATTEC），为亨廷顿病等衰老疾病的根本性治疗干预提供了新策略。.在本项目的资助下，项目负责人作为通讯作者发表相关论文于Nature、Nature Chemical Biology、Cell Research、Brain等著名期刊，总影响因子约150。成果被Huda Zoghbi等国际著名学者于Nature等期刊6次撰专文评述推荐。.综上所述，项目负责人聚焦于亨廷顿病等polyQ疾病的发生发展机制，揭示了疾病的源头机制、在衰老中向神经退行发展的机制，以及潜在的干预策略，取得了一系列有影响力的成果。