학술논문
Poly(ADP-ribose) promotes toxicity of C9ORF72arginine-rich dipeptide repeat proteins
Document Type
Article
Author
Gao, Junli; Mewborne, Quinlan T.; Girdhar, Amandeep; Sheth, Udit; Coyne, Alyssa N.; Punathil, Ritika; Kang, Bong Gu; Dasovich, Morgan; Veire, Austin; DeJesus Hernandez, Mariely; Liu, Shuaichen; Shi, Zheng; Dafinca, Ruxandra; Fouquerel, Elise; Talbot, Kevin; Kam, Tae-In; Zhang, Yong-Jie; Dickson, Dennis; Petrucelli, Leonard; van Blitterswijk, Marka; Guo, Lin; Dawson, Ted M.; Dawson, Valina L.; Leung, Anthony K. L.; Lloyd, Thomas E.; Gendron, Tania F.; Rothstein, Jeffrey D.; Zhang, Ke
Source
Science Translational Medicine; September 2022, Vol. 14 Issue: 662
Subject
Language
ISSN
19466234; 19466242
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.