Citations 2
Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins
Gao, Junli , Mewborne, Quinlan T. , Girdhar, Amandeep , Sheth, Udit , Coyne, Alyssa N. , Punathil, Ritika , Kang, Bong Gu , Dasovich, Morgan , Veire, Austin M. , Hernandez, Mariely DeJesus, Liu, Shuaichen , Shi, Zheng , Dafinca, Ruxandra , Talbot, Kevin , Zhang, Yong‐Jie , Petrucelli, Leonard , Blitterswijk, Marka van , Guo, Lin , Dawson, Ted M. , Veire, Austin , DeJesus Hernandez, Mariely, Fouquerel, Elise , Talbot, Kevin , Kam, Tae-In , Zhang, Yong-Jie , Dickson, Dennis W , 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 , Coyne, Alyssa N , Sheth, Udit , Liu, Shuaichen, Kam, Tae‐In , Dickson, Dennis W. , Dawson, Valina L. , Gendron, Tania F. , Rothstein, Jeffrey D. , Zhang, Ke
Science Translational Medicine | September 14, 2022 | Volume: 14 | Issue: 662 | Pages: No page available
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.
Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity
Zhang, Yong‐Jie , Guo, Lin , Gonzales, Patrick , Gendron, Tania F. , Wu, Yanwei , Jansen‐West, Karen , O’Raw, Aliesha D. , Pickles, Sarah , Prudencio, Mercedes , Carlomagno, Yari , Gachechiladze, Mariam A. , Tian, Ruilin , Chew, Jeannie , DeTure, Michael , Lin, Wen-Lang, Tong, Jimei, Daughrity, Lillian M. , Yue, Mei, Song, Yuping , Andersen, Jonathan W. , Castanedes‐Casey, Monica , Kurti, Aishe, Antognetti, Giovanna, McCampbell, Alexander , Rademakers, Rosa , Oskarsson, Björn , Kampmann, Martin , Ward, Michael E. , Fryer, John Denis , Link, Christopher D. , Shorter, James , Petrucelli, Leonard , Gonzales, Patrick K , Pickles, Sarah R , Chew, Jeannie , DeTure, Michael , Daughrity, Lillian M , Castanedes-Casey, Monica , McCampbell, Alexander , Rademakers, Rosa , Oskarsson, Björn , Dickson, Dennis W , Kampmann, Martin , Ward, Michael E , Shorter, James , Petrucelli, Leonard , Zhang, Yong-Jie , Prudencio, Mercedes , O'Raw, Aliesha , Gendron, Tania F , Guo, Lin , Ludwig, Connor , Datta, Abhishek, Dickson, Dennis W.
Science | February 15, 2019 | Volume: 363 | Issue: 6428 | Pages: No page available
How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606