Proline‐arginine poly‐dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9‐ALS/FTD). Unconventional translation of the hexanucleotide repeat expansion generates five dipeptide repeat proteins (DPRs). The molecular mechanism underlying the DPR‐linked neurotoxicity is under investigation. In this study, using cell‐based models, we show that poly‐proline‐arginine DPR (poly‐PR), the most neurotoxic DPR in vitro, binds to adenosine deaminase acting on RNA (ADAR)1p110 and ADAR2 and inhibits their RNA editing activity. We further show that poly‐PR impairs cellular stress response that is mediated by ADAR1p110. These results together suggest that the poly‐PR‐mediated inhibition of the ADAR activity contributes to C9‐ALS/FTD‐linked neurotoxicity. Poly‐proline‐arginine (PR), a neurotoxic dipeptide repeat protein derived from C9orf72 mutation, binds to adenosine deaminase acting on RNA (ADAR)1 and ADAR2. Poly‐PR inhibits their RNA editing activity. Poly‐PR also impairs cellular stress response mediated by ADAR1. These results suggest that poly‐PR causes neurotoxicity by dysregulating the function of ADARs.