| Autor: |
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 |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 9/14/2022, Vol. 14 Issue 662, p1-15, 15p |
| Abstrakt: |
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. Bringing the target up to PAR: The most common genetic form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/LTD) is caused by repeat expansion of the hexanucleotide G4C2 in the C9ORF72 gene, the subsequent production of arginine-rich dipeptide repeat proteins (R-DPRs) ultimately resulting in neurodegeneration. Here, Gao et al. investigated how R-DPR formation could lead to neuronal loss and showed that the polymer poly(ADP)-ribose (PAR) interacts with R-DPR and promotes stress granule formation and TDP-43 aggregation in fly models. Similar effects were found in samples from patients with ALS/FTD, suggesting that targeting PAR could reduce the deleterious effects of R-DPR in C9ORF72-mediated ALS/FTD. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
