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Neuron. 2013 May 8;78(3):440-55. doi: 10.1016/j.neuron.2013.03.026. Epub 2013 Apr 18.

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

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  • 1Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. petertod@umich.edu

Erratum in

  • Neuron. 2013 Jul 24;79(2):402.

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 by eliminating 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.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID:
23602499
[PubMed - indexed for MEDLINE]
PMCID:
PMC3831531
Free PMC Article
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