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

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

SUBMITTER: Yang J 

PROVIDER: S-EPMC12603922 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature