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

Jason Yang¹, Yunhan Xu¹, David R Ziehr^{1

2

3}, Martin S Taylor⁴, Max L Valenstein^{1

2

3}, Evgeni M Frenkel⁵, Jack R Bush¹, Kate Rutter¹, Igor Stevanovski^{6

7}, Charlie Y Shi^{8

9

10}, Maheswaran Kesavan^{1

11}, Ricardo Mouro Pinto^{1

2

12}, Ira Deveson^{6

7

13}, David P Bartel^{8

9

10}, David M Sabatini⁵, Raghu R Chivukula^{1

2

3

14

15}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁵ Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
⁶ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁷ Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Darlinghurst, NSW, Australia.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁹ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹¹ Molecular Medicine Program, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
¹² Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
¹⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.

PMID: 40674500
DOI: 10.1126/science.ado2403

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

Jason Yang et al. Science. 2025.

. 2025 Jul 17;389(6757):eado2403.

doi: 10.1126/science.ado2403. Epub 2025 Jul 17.

Authors

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁵ Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
⁶ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁷ Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Darlinghurst, NSW, Australia.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁹ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹¹ Molecular Medicine Program, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
¹² Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
¹⁴ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.

PMID: 40674500
DOI: 10.1126/science.ado2403

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

Affiliations

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

Authors

Affiliations

Abstract

MeSH terms

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LinkOut - more resources

Molecular Biology Databases