Expansion of an intronic (GGGGCC) n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

The original version of this article contained errors in Figs. 2A, 3A and 3B that were inadvertently introduced during typesetting. The third sample of Fig 2A, the third panel of Fig 3A, and the third sample of Fig 3B were inadvertently labelled (G 4 C 2 ) 100 RNA rather than (G 2 C 4 ) 100 RNA. In addition, the fifth sample of Fig 2A were inadvertently labelled GA 50 -GFP and rather than GR 50 -GFP. These errors have now been corrected in both the PDF and HTML versions of the article.