Department of Biology and Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Nat Cell Biol. 2024 Jun;26(6):892-902. doi: 10.1038/s41556-024-01414-x. Epub 2024 May 13.
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，由亨廷顿（HTT）基因中 CAG 三核苷酸重复扩展引起，该基因编码一个同聚多谷氨酰胺（polyQ）片段。尽管突变 HTT（mHTT）蛋白已知会聚集，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 的翻译和聚集都受到应激反应的上游开放阅读框的调节，并且 polyQ 扩展导致无意义的翻译终止和释放易聚集的截断 mHTT 片段。值得注意的是，我们发现 mHTT 会耗尽症状性 HD 小鼠和培养的 HD 细胞中翻译延伸因子 eIF5A，导致核糖体普遍暂停和碰撞。eIF5A 的缺失破坏了体内平衡的控制，并且损害了从急性应激中恢复。重要的是，抑制翻译起始的药物可减少过早终止，并减轻这种加剧的核糖毒性应激和 HD 功能障碍级联反应。
