Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins.
Junli GaoQuinlan T MewborneAmandeep GirdharUdit ShethAlyssa N CoyneRitika PunathilBong Gu KangMorgan DasovichAustin M VeireMariely DeJesus HernandezShuaichen LiuZheng ShiRuxandra DafincaElise FouquerelKevin TalbotTae-In KamYong-Jie ZhangGourisankar GhoshLeonard PetrucelliMarka van BlitterswijkLin GuoTed M DawsonValina L DawsonAnthony K L LeungThomas E LloydTania F GendronJeffrey D RothsteinKe ZhangPublished in: Science translational medicine (2022)
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.
Keyphrases
- amyotrophic lateral sclerosis
- end stage renal disease
- induced pluripotent stem cells
- nitric oxide
- oxidative stress
- newly diagnosed
- ejection fraction
- induced apoptosis
- chronic kidney disease
- transcription factor
- prognostic factors
- gene expression
- peritoneal dialysis
- high glucose
- endothelial cells
- signaling pathway
- genome wide
- diabetic rats
- copy number
- drug induced
- cell death