Poly(ADP-ribose) promotes toxicity of <i>C9ORF72</i> arginine-rich dipeptide repeat proteins-Reference-Cited by-同舟云学术

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

Published:2022-09-14 Issue:662 Volume:14 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Gao Junli¹^ORCID,Mewborne Quinlan T.¹^ORCID,Girdhar Amandeep²^ORCID,Sheth Udit¹^ORCID,Coyne Alyssa N.³⁴^ORCID,Punathil Ritika¹^ORCID,Kang Bong Gu³^ORCID,Dasovich Morgan⁵⁶^ORCID,Veire Austin¹^ORCID,DeJesus Hernandez Mariely¹,Liu Shuaichen⁵,Shi Zheng⁷^ORCID,Dafinca Ruxandra⁸^ORCID,Fouquerel Elise²^ORCID,Talbot Kevin⁸^ORCID,Kam Tae-In³^ORCID,Zhang Yong-Jie¹^ORCID,Dickson Dennis¹^ORCID,Petrucelli Leonard¹⁹^ORCID,van Blitterswijk Marka¹^ORCID,Guo Lin²^ORCID,Dawson Ted M.³¹⁰¹¹^ORCID,Dawson Valina L.³¹⁰¹¹^ORCID,Leung Anthony K. L.⁵¹²¹³¹⁴^ORCID,Lloyd Thomas E.³¹¹^ORCID,Gendron Tania F.¹⁹^ORCID,Rothstein Jeffrey D.³⁴¹¹^ORCID,Zhang Ke¹⁹¹⁵^ORCID

Affiliation:

1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

2. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

3. Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

4. Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

5. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

6. Department of Chemistry, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.

7. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.

8. Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

9. Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA.

10. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

11. Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

12. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

13. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

14. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

15. Institute of Neurological Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518132, China.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Reference85 articles.

1. Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

2. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

3. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins

4. The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS

5. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia

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