Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.
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| Title: | Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders. |
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| Authors: | 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. |
| Source: | Science. 7/17/2025, Vol. 389 Issue 6757, p1-20. 20p. |
| Subjects: | Transfer RNA, Neurodegeneration, Proteomics, RNA splicing, Trinucleotide repeats |
| 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. Editor's summary: Multiple neurological disorders are caused by noncoding expansions of GCC repeats at different loci. These repeats generate peptides containing polyglycine (polyGly) components that have been thought to promote toxicity and neurodegeneration. Using in vitro preparations, Yang et al. showed that polyGly peptides cause toxic aggregates that recruit the entire transfer RNA (tRNA) ligase complex (tRNA-LC) through FAM98B, a subunit of the tRNA-LC with unknown functions (see the Perspective by Kapur and Ackerman). Importantly, in tissue from patients affected by polyGly-related disorders, the authors identified FAM98B depletion and tRNA-processing defects, suggesting a pathological link between protein aggregation and tRNA biogenesis defects. —Mattia Maroso INTRODUCTION: Although protein aggregates are a hallmark of neurodegenerative diseases, their roles in pathogenesis remain controversial. Recent work has revealed that various GGC repeat expansions underlie a family of neurodegenerative disorders characterized by intranuclear protein aggregates in neurons as well as other cell types. Although initially thought to reside in noncoding regions of the genome, several expanded GGC repeats are now known to be translated into proteins containing aggregation-prone polyglycine (polyGly) tracts. These polyGly-containing proteins are present within intranuclear inclusions of patients with GGC repeat diseases and are toxic when expressed in animal models, suggesting that their production may contribute to neurodegeneration. RATIONALE: The two best-characterized GGC repeat diseases are fragile X-associated tremor/ataxia syndrome (FXTAS) and neuronal intranuclear inclusion disease (NIID), which are nearly indistinguishable clinically. Given their striking similarity despite their causal loci sharing only GGC repeats in common, we reasoned that the contributions of polyGly-containing proteins to neurodegeneration in these two diseases might be attributable to their polyGly tracts per se rather than any flanking host locus sequence. We therefore developed a system to express artificial expanded polyGly proteins, purify the resulting protein aggregates, and profile their composition. RESULTS: We found that polyGly aggregates preferentially recruit endogenous proteins containing glycine-rich intrinsically disordered regions (IDRs). Notably, among the most highly enriched of such endogenous proteins was family with sequence similarity 98 member B (FAM98B), which harbors the single most glycine-rich sequence in the entire human proteome. FAM98B is a component of the transfer RNA (tRNA) ligase complex (tRNA-LC), which catalyzes a key step in the biogenesis of intron-containing tRNAs. Through the glycine-rich IDR of FAM98B, polyGly aggregation sequesters and depletes the tRNA-LC from the soluble nucleoplasm, resulting in impaired ligation of tRNA exons. To explore whether this process might represent a unifying pathogenic mechanism across different GGC repeat diseases, we examined tissue samples from individuals with FXTAS or NIID. In both diseases, tRNA-LC components were recruited to intranuclear inclusions and depleted from the soluble nucleoplasm. Lastly, to directly test whether impairment of tRNA ligation could contribute to neuropathology, we depleted Fam98b from the brains of adult mice. These animals developed severe motor coordination defects and widespread gliosis, which are key signs and symptoms of neurodegenerative GGC repeat diseases in humans. CONCLUSION: These data suggest a pathogenic mechanism wherein polyGly-containing proteins produced from expanded GGC repeats interact with the glycine-rich IDR of FAM98B to sequester and deplete the tRNA-LC. Loss of tRNA ligase activity could contribute to cellular toxicity through insufficient production of mature spliced tRNAs or accumulation of tRNA splicing intermediates, ultimately resulting in neurodegeneration. Consistent with this model, mutations in other tRNA splicing pathway components cause a group of severe prenatal-onset neurodegenerative diseases exhibiting substantial phenotypic overlap with GGC repeat disorders. Our work thus suggests a mechanistic link between protein aggregation in GGC repeat disorders and inherited defects in tRNA processing machinery previously known to cause neurodegeneration. Notably, these findings raise the possibility that restoration of tRNA ligation might represent a therapeutic strategy applicable across GGC repeat diseases caused by expansions at different loci. Neurodegenerative GGC repeat expansions disrupt tRNA processing through aggregation of a singularly glycine-rich disordered region in FAM98B.: In normal tRNA splicing, exons are ligated by the tRNA ligase complex, a heteropentameric complex containing FAM98B. PolyGly proteins produced in GGC repeat disorders interact with FAM98B, which harbors the single most glycine-rich sequence in the human proteome, resulting in sequestration and depletion of the tRNA ligase complex. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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