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

共 84 条

[21] Identifying Poly(ADP-ribose)-Binding Proteins with Photoaffinity-Based Proteomics [J].

Dasovich, Morgan ;

Beckett, Morgan Q. ;

Bailey, Scott ;

Ong, Shao-En ;

Greenberg, Marc M. ;

Leung, Anthony K. L. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2021, 143 (08) :3037-3042

[22] Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS [J].

DeJesus-Hernandez, Mariely ;

Mackenzie, Ian R. ;

Boeve, Bradley F. ;

Boxer, Adam L. ;

Baker, Matt ;

Rutherford, Nicola J. ;

Nicholson, Alexandra M. ;

Finch, NiCole A. ;

Flynn, Heather ;

Adamson, Jennifer ;

Kouri, Naomi ;

Wojtas, Aleksandra ;

Sengdy, Pheth ;

Hsiung, Ging-Yuek R. ;

Karydas, Anna ;

Seeley, William W. ;

Josephs, Keith A. ;

Coppola, Giovanni ;

Geschwind, Daniel H. ;

Wszolek, Zbigniew K. ;

Feldman, Howard ;

Knopman, David S. ;

Petersen, Ronald C. ;

Miller, Bruce L. ;

Dickson, Dennis W. ;

Boylan, Kevin B. ;

Graff-Radford, Neill R. ;

Rademakers, Rosa .

NEURON, 2011, 72 (02) :245-256

[23] RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention [J].

Donnelly, Christopher J. ;

Zhang, Ping-Wu ;

Pham, Jacqueline T. ;

Heusler, Aaron R. ;

Mistry, Nipun A. ;

Vidensky, Svetlana ;

Daley, Elizabeth L. ;

Poth, Erin M. ;

Hoover, Benjamin ;

Fines, Daniel M. ;

Maragakis, Nicholas ;

Tienari, Pentti J. ;

Petrucelli, Leonard ;

Traynor, Bryan J. ;

Wang, Jiou ;

Rigo, Frank ;

Bennett, C. Frank ;

Blackshaw, Seth ;

Sattler, Rita ;

Rothstein, Jeffrey D. .

NEURON, 2013, 80 (02) :415-428

[24] PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins [J].

Duan, Yongjia ;

Du, Aiying ;

Gu, Jinge ;

Duan, Gang ;

Wang, Chen ;

Gui, Xinrui ;

Ma, Zhiwei ;

Qian, Beituo ;

Deng, Xue ;

Zhang, Kai ;

Sun, Le ;

Tian, Kuili ;

Zhang, Yaoyang ;

Jiang, Hong ;

Liu, Cong ;

Fang, Yanshan .

CELL RESEARCH, 2019, 29 (03) :233-247

[25] Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS [J].

Elden, Andrew C. ;

Kim, Hyung-Jun ;

Hart, Michael P. ;

Chen-Plotkin, Alice S. ;

Johnson, Brian S. ;

Fang, Xiaodong ;

Armakola, Maria ;

Geser, Felix ;

Greene, Robert ;

Lu, Min Min ;

Padmanabhan, Arun ;

Clay-Falcone, Dana ;

McCluskey, Leo ;

Elman, Lauren ;

Juhr, Denise ;

Gruber, Peter J. ;

Rueb, Udo ;

Auburger, Georg ;

Trojanowski, John Q. ;

Lee, Virginia M. -Y. ;

Van Deerlin, Vivianna M. ;

Bonini, Nancy M. ;

Gitler, Aaron D. .

NATURE, 2010, 466 (7310) :1069-U77

[26] Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation [J].

Fernandes, Nikita ;

Nero, Luke ;

Lyons, Shawn M. ;

Ivanov, Pavel ;

Mittelmeier, Telsa M. ;

Bolger, Timothy A. ;

Buchan, J. Ross .

BIOMOLECULES, 2020, 10 (10) :1-19

[27] Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers [J].

Gendron, Tania F. ;

van Blitterswijk, Marka ;

Bieniek, Kevin F. ;

Daughrity, Lillian M. ;

Jiang, Jie ;

Rush, Beth K. ;

Pedraza, Otto ;

Lucas, John A. ;

Murray, Melissa E. ;

Desaro, Pamela ;

Robertson, Amelia ;

Overstreet, Karen ;

Thomas, Colleen S. ;

Crook, Julia E. ;

Castanedes-Casey, Monica ;

Rousseau, Linda ;

Josephs, Keith A. ;

Parisi, Joseph E. ;

Knopman, David S. ;

Petersen, Ronald C. ;

Boeve, Bradley F. ;

Graff-Radford, Neill R. ;

Rademakers, Rosa ;

Lagier-Tourenne, Clotilde ;

Edbauer, Dieter ;

Cleveland, Don W. ;

Dickson, Dennis W. ;

Petrucelli, Leonard ;

Boylan, Kevin B. .

ACTA NEUROPATHOLOGICA, 2015, 130 (04) :559-573

[28] Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS [J].

Gendron, Tania F. ;

Bieniek, Kevin F. ;

Zhang, Yong-Jie ;

Jansen-West, Karen ;

Ash, Peter E. A. ;

Caulfield, Thomas ;

Daughrity, Lillian ;

Dunmore, Judith H. ;

Castanedes-Casey, Monica ;

Chew, Jeannie ;

Cosio, Danielle M. ;

van Blitterswijk, Marka ;

Lee, Wing C. ;

Rademakers, Rosa ;

Boylan, Kevin B. ;

Dickson, Dennis W. ;

Petrucelli, Leonard .

ACTA NEUROPATHOLOGICA, 2013, 126 (06) :829-844

[29] Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD [J].

Goodman, Lindsey D. ;

Prudencio, Mercedes ;

Kramer, Nicholas J. ;

Martinez-Ramirez, Luis F. ;

Srinivasan, Ananth R. ;

Lan, Matthews ;

Parisi, Michael J. ;

Zhu, Yongqing ;

Chew, Jeannie ;

Cook, Casey N. ;

Berson, Amit ;

Gitler, Aaron D. ;

Petrucelli, Leonard ;

Bonini, Nancy M. .

NATURE NEUROSCIENCE, 2019, 22 (06) :863-+

[30] eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS [J].

Goodman, Lindsey D. ;

Prudencio, Mercedes ;

Srinivasan, Ananth R. ;

Rifai, Olivia M. ;

Lee, Virginia M. -Y. ;

Petrucelli, Leonard ;

Bonini, Nancy M. .

ACTA NEUROPATHOLOGICA COMMUNICATIONS, 2019, 7 (1) :62

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