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

Junli Gao, Quinlan T. Mewborne, Amandeep Girdhar, Udit Sheth, Alyssa N. Coyne, Ritika Punathil, Bong Gu Kang, Morgan Dasovich, Austin Veire, Mariely DeJesus Hernandez, Shuaichen Liu, Zheng Shi, Ruxandra Dafinca, Elise Fouquerel, Kevin Talbot, Tae In Kam, Yong Jie Zhang, Dennis Dickson, Leonard Petrucelli, Marka van BlitterswijkLin Guo, Ted M. Dawson, Valina L. Dawson, Anthony K.L. Leung, Thomas E. Lloyd, Tania F. Gendron, Jeffrey D. Rothstein, Ke Zhang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numberabq3215
JournalScience translational medicine
Issue number662
StatePublished - Sep 14 2022

ASJC Scopus subject areas

  • Medicine(all)


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