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Elsevier (Cell Press), Neuron, 3(78), p. 440-455

DOI: 10.1016/j.neuron.2013.03.026

Elsevier (Cell Press), Neuron, 2(79), p. 402

DOI: 10.1016/j.neuron.2013.07.008

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CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 50 UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiqui- tin-positive neuronal inclusions, a pathologic hall- mark 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 ubiq- uitin-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 pro- vide evidence that RAN translation contributes to neurodegeneration.