DNA and RNA binding mediate the toxicity of arginine-rich peptides encoded by C9ORF72 GGGGCC repeats

Expanded intronic GGGGCC sequences in C9ORF72 found in patients of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are translated into several dipeptide-repeat polypeptides (DPRs), from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS/FTD, its mechanism remains unknown. We here show that (PR)n polypeptides bind DNA and RNA, so that any reaction involving nucleic acids is impaired by the DPRs. Consistently, (PR)n-induced cell death is rescued by addition of non-coding oligonucleotides. Interestingly, the effects of (PR)n are mimicked by protamine, a sperm-specific arginine-rich protein with affinity for nucleic acids, and the toxicity of either protamine or (PR)n DPRs is rescued by the anticoagulant heparin. We propose that generalized coating of nucleic acids by arginine-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS/FTD.