Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-17 DOI:10.1126/science.ado2403

Jason Yang, Yunhan Xu, David R. Ziehr, Martin S. Taylor, Max L. Valenstein, Evgeni M. Frenkel, Jack R. Bush, Kate Rutter, Igor Stevanovski, Charlie Y. Shi, Maheswaran Kesavan, Ricardo Mouro Pinto, Ira Deveson, David P. Bartel, David M. Sabatini, Raghu R. Chivukula

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Abstract

Aggregation-prone polyglycine-containing proteins produced from expanded GGC repeats are implicated in an emerging family of neurodegenerative disorders. In this study, we showed that polyglycine itself forms aggregates that incorporate endogenous glycine-rich proteins, including FAM98B, a component of the transfer RNA (tRNA) ligase complex (tRNA-LC) that harbors the most glycine-rich sequence in the human proteome. Through this glycine-rich intrinsically disordered region (IDR), polyglycine sequesters and depletes the tRNA-LC, disrupting tRNA processing. Accordingly, patient tissues revealed aggregate-associated FAM98B depletion and accumulation of aberrant tRNA splicing intermediates. Furthermore, Fam98b depletion in adult mice caused progressive motor coordination deficits and hindbrain pathology. Our data suggest that the FAM98B glycine-rich IDR mechanistically links previously disparate neurodegenerative disorders of protein aggregation and tRNA processing.

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聚甘氨酸介导的FAM98B聚集破坏GGC重复疾病中的tRNA加工

由扩展的GGC重复序列产生的易聚集的含聚甘氨酸蛋白与新出现的神经退行性疾病家族有关。在这项研究中，我们发现聚甘氨酸本身形成聚集体，结合内源性富含甘氨酸的蛋白质，包括FAM98B，这是转移RNA （tRNA）连接酶复合物（tRNA- lc）的一个组成部分，在人类蛋白质组中含有最富含甘氨酸的序列。通过这个富含甘氨酸的内在无序区（IDR），聚甘氨酸隔离并消耗tRNA- lc，破坏tRNA加工。因此，患者组织显示出与聚集体相关的FAM98B耗竭和异常tRNA剪接中间体的积累。此外，成年小鼠的Fam98b缺失导致进行性运动协调缺陷和后脑病理。我们的数据表明，FAM98B富含甘氨酸的IDR在机制上连接了以前不同的蛋白质聚集和tRNA加工的神经退行性疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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