Increased accumulation of Staufen in nucleus contributes to C9ALS/FTD pathology

Abstract

G4C2 repeat expansion mutation of C9orf72 is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA G4C2 repeats produce 5 dipeptide repeat (DPR) proteins via repeat-associated non-ATG translation. Arginine-rich DPR proteins such as polyGly-Arg (GR) and polyPro-Arg (PR) are highly toxic and can perturb the dynamics and functions of various RNA binding proteins (RBPs). Recently, Staufen, a double-stranded RNA binding protein, was identified as one of the top interactors of poly (GR) and poly (PR), but the way in which Staufen mediates toxicity is currently unknown. Here, we show that poly (GR) and poly (PR) cause RNA-dependent nuclear accumulation of Staufen. Taken together, these data suggest that nuclear accumulation of Staufen may contribute to C9ALS/FTD pathogenesis.