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

被引：13

作者：

Gao, Junli ^{[1
]}

Mewborne, Quinlan T. ^{[1
]}

Girdhar, Amandeep ^{[2
]}

Sheth, Udit ^{[1
]}

Coyne, Alyssa N. ^{[3
,4
]}

Punathil, Ritika ^{[1
]}

Kang, Bong Gu ^{[3
]}

Dasovich, Morgan ^{[5
,6
]}

Veire, Austin ^{[1
]}

Hernandez, Mariely DeJesus ^{[1
]}

Liu, Shuaichen ^{[5
]}

Shi, Zheng ^{[7
]}

Dafinca, Ruxandra ^{[8
]}

Fouquerel, Elise ^{[2
]}

Talbot, Kevin ^{[8
]}

Kam, Tae-In ^{[3
]}

Zhang, Yong-Jie ^{[1
]}

Dickson, Dennis ^{[1
]}

Petrucelli, Leonard ^{[1
,9
]}

Van Blitterswijk, Marka ^{[1
]}

Guo, Lin ^{[2
]}

Dawson, Ted M. ^{[3
,10
,11
]}

Dawson, Valina L. ^{[3
,10
,11
]}

Leung, Anthony K. L. ^{[5
,12
,13
,14
,15
]}

Lloyd, Thomas E. ^{[3
,11
]}

Gendron, Tania F. ^{[1
,9
]}

Rothstein, Jeffrey D. ^{[3
,4
,11
]}

Zhang, Ke ^{[1
,9
,15
]}

机构：

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Brain Sci Inst, Sch Med, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Krieger Sch Arts & Sci, Dept Chem, Baltimore, MD 21218 USA

[7] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA

[8] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[9] Mayo Clin, Neurosci Grad Program, Grad Sch Biomed Sci, Jacksonville, FL 32224 USA

[10] Johns Hopkins Univ, Inst Cell Engn, Sch Med, Neuro Regenerat & Stem Cell Programs, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ, McKusick Nathans Dept Genet Med, Sch Med, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Dept Oncol, Sch Med, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Dept Mol Biol & Genet, Sch Med, Baltimore, MD 21205 USA

[15] Shenzhen Bay Lab, Inst Neurol Dis, Shenzhen 518132, Guangdong, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2022年 / 14卷 / 662期

关键词：

HEXANUCLEOTIDE REPEAT; PHASE-SEPARATION; ANTISENSE TRANSCRIPTS; GGGGCC REPEAT; RNA FOCI; STRESS; EXPANSION; NEURODEGENERATION; TDP-43; ALS;

D O I：

10.1126/scitranslmed.abq3215

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：15

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