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J Biol Chem. 2019 Oct 23. pii: jbc.RA119.009951. doi: 10.1074/jbc.RA119.009951. [Epub ahead of print]

High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation.

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University of Michigan, United States.
Neurology, University of Michigan, United States.


Repeat-associated non-AUG (RAN) translation is a non-canonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X-associated tremor ataxia syndrome (FXTAS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using circular dichroism and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.


C9orf72; FXTAS; Lou Gehrig's Disease; RAN translation; RNA; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); drug screening; neurodegeneration; small molecule; translation

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