CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome

Peter K. Todd, Seok Yoon Oh, Amy Krans, Fang He, Chantal Sellier, Michelle Frazer, Abigail J. Renoux, Kai chun Chen, K. Matthew Scaglione, Venkatesha Basrur, Kojo Elenitoba-Johnson, Jean P. Vonsattel, Elan D. Louis, Michael A. Sutton, J. Paul Taylor, Ryan E. Mills, Nicholas Charlet-Berguerand, Henry L. Paulson

Research output: Contribution to journalArticlepeer-review

270 Scopus citations

Abstract

Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5@ UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed byeliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration

Original languageEnglish (US)
Pages (from-to)440-455
Number of pages16
JournalNeuron
Volume78
Issue number3
DOIs
StatePublished - May 8 2013
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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