A GGGGCC hexanucleotide repeat expansion within the non-coding region of the C9orf72 gene is frequently linked to the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Unconventional translation of the hexanucleotide repeat expansion generates five dipeptide repeat proteins (DPRs) including poly-proline-arginine (poly-PR). DPRs accumulate in the neurons of C9-ALS/FTD patients and are hypothesized to be toxic to the neurons. In this study, we show that poly-PR, the most neurotoxic DPR in vitro, interacts with both adenosine deaminase acting on RNA (ADAR)1 and ADAR2 and inhibits their RNA editing activity. We further show that poly-PR impairs cellular stress response mediated by ADAR1. Combined with the finding that the loss-of-function of ADARs causes cytotoxicity, these results suggest that poly-PR-mediated inhibition of the ADAR activity contributes to C9-ALS/FTD-linked neurotoxicity.