聚谷氨酰胺病（Polyglutamine diseases）是指由包含谷氨酰胺重复扩增序列的变异蛋白所导致的一类神经退行性疾病，主要包括亨廷顿病和脊髓小脑性共济失调症等。目前，聚谷氨酰胺致病蛋白polyQ毒性机制仍不清楚。前期采用原创性生物化学技术在亨廷顿病中证实PolyQ蛋白构象的多态性现象，polyQ抗体3B5H10所识别PolyQ蛋白构象缺乏泛素K63修饰而抵抗选性自噬途径降解（Fu et al., Nat Chem Biol, 2017）。本项目拟验证致病PolyQ蛋白构象多态性在脊髓小脑性共济失调症1型和3型中是否也存在，重点揭示聚谷氨酰胺病polyQ蛋白不同构象泛素差异修饰机制，基于构象多态性建立测量选择性自噬方法和筛选构象改变化合物，并阐明化合物作用。因此，本项目将揭示致病PolyQ蛋白构象多态性的生物学机制并实现其应用，为此类疾病研究和构象药物研发提供理论依据。

Polyglutamine diseases refer to a kind of neurodegenerative diseases caused by mutant proteins with abnormal expansion of trinucleotide repeats, including Huntington's disease and Spinocerebellar ataxia types. etc. At present, the toxicity mechanism of polyglutamine pathogenic protein polyQ is still unclear. In previous study, the polymorphism and toxicity of polyQ protein conformation were confirmed in Huntington's disease by original biochemical techniques. The polyQ protein conformation identified by polyQ antibody 3B5H10 lacks ubiquitin K63 modification and then resists selective autophagy pathway degradation (Fu et al., Nat Chem Biol, 2017). Here, this project firstly validate whether the conformational polymorphism of pathogenic polyQ protein exists in spinocerebellar ataxia type 1 and type 3, we focus on revealing the mechanism for ubiquitin differential modification of different conformational polyQ protein in polyglutamine diseases, and further to develop a method for measuring selective autophagy and screening conformational change compounds based on conformational polymorphism. Therefore, this project will reveal the mechanism for conformational polymorphism of pathogenic PolyQ protein and its applications, which will provide theoretical basis for the investigation of polyglutamine diseases and the development of conformational drugs.