Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type HTT and mHTT are regulated by a stress-responsive upstream open reading frame and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

亨廷顿病 (HD) 是一种神经退行性疾病，由编码同聚聚谷氨酰胺 (polyQ) 序列的亨廷顿 ( HTT ) 基因中 CAG 三核苷酸重复序列的扩增引起。尽管已知突变型 HTT (mHTT) 蛋白会聚集，但聚集与神经毒性之间的联系仍不清楚。在这里，我们表明野生型 HTT 和 mHTT 的翻译和聚集均受到应激反应性上游开放阅读框的调节，并且 PolyQ 扩展导致翻译终止和截短的、易于聚集的 mHTT 片段的释放。值得注意的是，我们发现 mHTT 会耗尽有症状 HD 小鼠和培养的 HD 细胞大脑中的翻译延伸因子 eIF5A，导致普遍的核糖体暂停和碰撞。 eIF5A 的缺失会扰乱体内平衡控制并损害急性应激后的恢复。重要的是，抑制翻译起始的药物可以减少过早终止，并减轻 HD 中核糖毒性应激和功能障碍的级联升级。