美国斯坦福大学Judith Frydman小组取得一项新突破。他们的研究发现聚谷氨酰胺介导的核毒性破坏了亨廷顿病蛋白质平衡和应激反应。这一研究成果于2024年5月13日发表在国际顶尖学术期刊《自然—细胞生物学》上。

据介绍，亨廷顿氏病(HD)是一种神经退行性疾病，由亨廷顿蛋白(HTT)基因中CAG三核苷酸重复扩增引起，该基因编码一种多聚谷氨酰胺(polyQ)通道。虽然已知突变的HTT (mHTT)蛋白聚集，但聚集与神经毒性之间的联系尚不清楚。

本研究表明，野生型HTT和mHTT的翻译和聚集都受到应激响应的上游开放阅读框的调节，并且polyQ扩增导致翻译终止和易于聚集的截断mHTT片段的释放。值得注意的是，该研究组发现mHTT在有症状的HD小鼠和培养的HD细胞的大脑中，消耗翻译延伸因子eIF5A，导致普遍的核糖体暂停和碰撞。eIF5A的缺失会破坏体内平衡控制并损害急性应激的恢复。重要的是，抑制翻译起始的药物减少了成熟前终止，减轻了HD这种不断升级的级联核毒性应激和功能障碍。

附：英文原文

Title: Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s disease

Author: Aviner, Ranen, Lee, Ting-Ting, Masto, Vincent B., Li, Kathy H., Andino, Raul, Frydman, Judith

Issue&Volume: 2024-05-13

Abstract: 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.

DOI: 10.1038/s41556-024-01414-x

Source: https://www.nature.com/articles/s41556-024-01414-x