Talk abstracts
Talk on Saturday 12:00-12:15pm submitted by Alexander Linsalata
DDX3X Modulates CGG-Associated RAN Translation and Neuronal Toxicity
Alexander E. Linsalata (University of Michigan), Fang He (Texas A&M University-Kingsville), Sam Natla (University of Michigan), Peter K. Todd (University of Michigan)
Abstract:
Repeat-associated, non-AUG (RAN) translation is a non-canonical mode of protein synthesis distinguished by its dependence on nucleotide-repeat expansions (NREs) and use of non-AUG start codons. It is associated with several neurodegenerative disorders, including Fragile X-associated tremor/ataxia syndrome (FXTAS). The mechanism of RAN translation 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 a Drosophila melanogaster model of FXTAS. We identified the DEAD-box RNA helicase belle/DDX3X as a modifier of both CGG repeat-induced toxicity and RAN translation. Disrupting belle/DDX3X selectively inhibited RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat-induced toxicity in Drosophila and primary rodent neurons. In addition, in-vitro translation experiments indicated that belle/DDX3X exerts this role co-translationally, rather than at an upstream step in gene expression. These findings implicate RNA secondary structure as a critical element mediating RAN translation and a potential target for treating repeat-associated neurodegeneration.
Keywords: RAN Translation, DDX3X, Neurodegeneration