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

• 成果类型: Article
• 署名作者: Yang, Jason; Xu, Yunhan; Ziehr, David R.; Taylor, Martin S.; Valenstein, Max L.; Frenkel, Evgeni M.; Bush, Jack R.; Rutter, Kate; Stevanovski, Igor; Shi, Charlie Y.; Kesavan, Maheswaran; Pinto, Ricardo Mouro; Deveson, Ira; Bartel, David P.; Sabatini, David M.; Chivukula, Raghu R.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Brown University; Czech Academy of Sciences; Institute of Organic Chemistry & Biochemistry of the Czech Academy of Sciences; Garvan Institute of Medical Research; Murdoch Children's Research Institute; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Laval University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of New South Wales Sydney; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8090
• DOI: 10.1126/science.ado2403
• 发表日期: 2025-07-17
• 关键词: cause pontocerebellar hypoplasia; messenger-rna; tremor/ataxia syndrome; translation; protein; mutations; binding; gene; reveals; exosome

摘要

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.