CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 2013 May 08;78(3):440-55
Date
04/23/2013Pubmed ID
23602499Pubmed Central ID
PMC3831531DOI
10.1016/j.neuron.2013.03.026Scopus ID
2-s2.0-84877331220 (requires institutional sign-in at Scopus site) 413 CitationsAbstract
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.
Author List
Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M, Renoux AJ, Chen KC, Scaglione KM, Basrur V, Elenitoba-Johnson K, Vonsattel JP, Louis ED, Sutton MA, Taylor JP, Mills RE, Charlet-Berguerand N, Paulson HLMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Ataxia
Brain
Cells, Cultured
Disease Models, Animal
Drosophila
Fragile X Mental Retardation Protein
Fragile X Syndrome
Humans
Nerve Degeneration
Neurons
Protein Biosynthesis
Tremor
Trinucleotide Repeat Expansion
