Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

Abstract

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.

Regulation of Biomolecular Condensates by Poly(ADP-ribose)

“…162,376 Consistent with the notion of PAR's neurotoxic effect, inhibitors of PARP1 or PARP5a activity appear to not only prevent TDP-43 aggregation and toxicity but also suppress R-DPR toxicity. 114,119,162,297,377 As discussed above in section Stress Granules Are Nucleated by PAR Readers and PAR Chains, the source of neurotoxic PAR in ALS/FTLD is unclear. It is possible that, like in Parkinson's disease, PARP1 activity initiates the parthanatos pathway, driving cell death.…”

“…In fact, PAR increases poly(GR)-induced TDP-43 aggregation, contributing to the overall toxicity. 162,376 Consistent with the notion of PAR's neurotoxic effect, inhibitors of PARP1 or PARP5a activity appear to not only prevent TDP-43 aggregation and toxicity but also suppress R-DPR toxicity. 114,119,162,297,377 As discussed above in section Stress Granules Are Nucleated by PAR Readers and PAR Chains, the source of neurotoxic PAR in ALS/FTLD is unclear.…”

“…For example, PAR associates with poly(GR) in vitro and in post-mortem brain tissue, and appears to promote poly(GR) condensation, suggesting a role of PAR in promoting dipeptide repeat toxicity in c9ALS/ FTD. 162 Furthermore, tandem RGG domains, such as those observed in FET family proteins, can coordinate PS by binding PAR with some RGG repeats and other proteins with other RGG repeats. Indeed, proteins with tri-RGG domains are particularly enriched among PAR readers.…”

“…PAR binding may prevent or promote individual RGG domains from interacting with other disordered regions, inhibiting or promoting PS, respectively. For example, PAR associates with poly­(GR) in vitro and in post-mortem brain tissue, and appears to promote poly­(GR) condensation, suggesting a role of PAR in promoting dipeptide repeat toxicity in c9ALS/FTD . Furthermore, tandem RGG domains, such as those observed in FET family proteins, can coordinate PS by binding PAR with some RGG repeats and other proteins with other RGG repeats.…”

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

“…Moreover, the study by Wouter et al also found that genomic toxicity induced by targeting ATM, ATR, or DNA topoisomerase can trigger the extensive aggregation of proteins with a propensity for liquid–liquid phase separation (LLPS), which can also be mitigated by the inhibition of PARylation [ 92 ]. In ALS, numerous studies have shown that PAR-mediated LLPS facilitates the fibrillation of aggregation-prone proteins and their maturation into insoluble precipitates over time [ 93 , 94 , 95 ]. For instance, PAR has been shown to promote LLPS of FUS, TDP43, and hnRNPA1 in both ex vivo and cellular settings, while increased concentrations of ALS-related proteins in droplets is able to promote their own pathological fibrosis [ 96 , 97 , 98 , 99 ].…”