Elimination of virus-like particles reduces protein aggregation and extends replicative lifespan in Saccharomyces cerevisiae

作者：Kara L. Schneider, Xiaoxiao Hao, Katharina Keuenhof, Lisa Larsson Berglund, Arthur Fischbach, Doryaneh Ahmadpour, Srishti Chawla, Patricia Gómez-Gejo, Johanna L. Höög, Per O. Widlund, Thomas Nyström · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2313538121 · 被引用次数：9 · 研究领域：Genetic Neurodegenerative Diseases、Fungal and yeast genetics research、DNA Repair Mechanisms

A major consequence of aging and stress, in yeast to humans, is an increased accumulation of protein aggregates at distinct sites within the cells. Using genetic screens, immunoelectron microscopy, and three-dimensional modeling in our efforts to elucidate the importance of aggregate annexation, we found that most aggregates in yeast accumulate near the surface of mitochondria. Further, we show that virus-like particles (VLPs), which are part of the retrotransposition cycle of Ty elements, are markedly enriched in these sites of protein aggregation. RNA interference-mediated silencing of Ty expression perturbed aggregate sequestration to mitochondria, reduced overall protein aggregation, mitigated toxicity of a Huntington's disease model, and expanded the replicative lifespan of yeast in a partially Hsp104-dependent manner. The results are in line with recent data demonstrating that VLPs might act as aging factors in mammals, including humans, and extend these findings by linking VLPs to a toxic accumulation of protein aggregates and raising the possibility that they might negatively influence neurological disease progression.