Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure–cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation–cytotoxicity relationship of polyQ proteins.

内源性蛋白质中扩展的聚谷氨酰胺（polyQ）延伸导致至少九种人类疾病。polyQ发病机理的结构基础是了解这些疾病基本机制的关键，但由于在单原子水平上缺乏polyQ蛋白结构，因此尚不清楚和有争议。已经提出了各种假说来解释具有polyQ扩展的致病蛋白的结构-细胞毒性关系，这主要是基于间接证据。在这里，我们将回顾这些假设及其支持证据，以及来自最近的结构生物学和化学生物学研究的其他见解，重点是研究最广泛的polyQ疾病蛋白Huntingtin（HTT）。最后，