Journal
EMBO REPORTS
Volume 20, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/embr.201847498
Keywords
DDX3X; eIF; Fragile X-associated tremor; ataxia syndrome; RAN translation; RNA helicase
Categories
Funding
- VA BLRD [1I21BX001841, 1I01BX003231]
- NIH [R01-NS097542, R01NS086810, T32GM007315, F31NS100302, F30NS098571, T32NS007222-35S1, 1P30AG053760-01, R01NS099280]
- Michigan Alzheimer's Disease Center and Protein Folding Disease Initiative
- Ann Arbor Active Against ALS
Ask authors/readers for more resources
A CGG trinucleotide repeat expansion in the 5 ' UTR of FMR1 causes the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). This repeat supports a non-canonical mode of protein synthesis known as repeat-associated, non-AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate-based screen of eukaryotic initiation factors and RNA helicases in cell-based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5 ' UTR. These include the DEAD-box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat-induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat-associated neurodegeneration.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available