The Hairpin Form of r(G₄C₂)^exp in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules.

ABSTRACT: The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G₄C₂ repeat [(G₄C₂)^exp] in C9ORF72. ALS/FTD-associated toxicity has been traced to the RNA transcribed from the repeat expansion [r(G₄C₂)^exp], which sequesters RNA-binding proteins (RBPs) and undergoes repeat-associated non-ATG (RAN) translation to generate toxic dipeptide repeats. Using in vitro and cell-based assays, we identified a small molecule (4) that selectively bound r(G₄C₂)^exp, prevented sequestration of an RBP, and inhibited RAN translation. Indeed, biophysical characterization showed that 4 selectively bound the hairpin form of r(G₄

SUBMITTER: Wang ZF 

PROVIDER: S-EPMC6386614 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature