LAUSR

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD. Description Poly(ADP-ribose) promotes the condensation and toxicity of C9ORF72 arginine-rich dipeptide repeat proteins and contributes to neurodegeneration. Bringing the target up to PAR The most common genetic form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/LTD) is caused by repeat expansion of the hexanucleotide G4C2 in the C9ORF72 gene, the subsequent production of arginine-rich dipeptide repeat proteins (R-DPRs) ultimately resulting in neurodegeneration. Here, Gao et al. investigated how R-DPR formation could lead to neuronal loss and showed that the polymer poly(ADP)-ribose (PAR) interacts with R-DPR and promotes stress granule formation and TDP-43 aggregation in fly models. Similar effects were found in samples from patients with ALS/FTD, suggesting that targeting PAR could reduce the deleterious effects of R-DPR in C9ORF72-mediated ALS/FTD.