C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Abstract

25Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated 26 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential 27 42 Staufen, may also be an important pathological feature of C9-ALS/FTD. 43 44 45 46 47 3 48 Author summary 49 Cytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common 50 pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia 51 (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded 52 (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-53 dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that 54 Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression 55 of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity 56 and further augmented by reduction in stau dosage, the gene encoding Staufen. When we 57 knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was 58 exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is 59 protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their 60 retinal degeneration and viability were largely rescued. Based on these data, we suggest that 61 nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that 62 reducing stau dosage is a promising therapeutic target.