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

Junli Gao; Quinlan T Mewborne; Amandeep Girdhar; Udit Sheth; Alyssa N Coyne; Ritika Punathil; Bong Gu Kang; Morgan Dasovich; Austin Veire; Mariely DeJesus Hernandez; Shuaichen Liu; Zheng Shi; Ruxandra Dafinca; Elise Fouquerel; Kevin Talbot; Tae-In Kam; Yong-Jie Zhang; Dennis Dickson; Leonard Petrucelli; Marka van Blitterswijk; Lin Guo; Ted M Dawson; Valina L Dawson; Anthony K L Leung; Thomas E Lloyd; Tania F Gendron; Jeffrey D Rothstein; Ke Zhang

doi:10.1126/scitranslmed.abq3215

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

Sci Transl Med. 2022 Sep 14;14(662):eabq3215. doi: 10.1126/scitranslmed.abq3215. Epub 2022 Sep 14.

Authors

Junli Gao¹, Quinlan T Mewborne¹, Amandeep Girdhar², Udit Sheth¹, Alyssa N Coyne^{3

4}, Ritika Punathil¹, Bong Gu Kang³, Morgan Dasovich^{5

6}, Austin Veire¹, Mariely DeJesus Hernandez¹, Shuaichen Liu⁵, Zheng Shi⁷, Ruxandra Dafinca⁸, Elise Fouquerel², Kevin Talbot⁸, Tae-In Kam³, Yong-Jie Zhang¹, Dennis Dickson¹, Leonard Petrucelli^{1

9}, Marka van Blitterswijk¹, Lin Guo², Ted M Dawson^{3

10

11}, Valina L Dawson^{3

10

11}, Anthony K L Leung^{5

12

13

14}, Thomas E Lloyd^{3

11}, Tania F Gendron^{1

9}, Jeffrey D Rothstein^{3

4

11}, Ke Zhang^{1

9

15}

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Arginine
C9orf72 Protein / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Dipeptides / metabolism
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / metabolism
Humans
Poly Adenosine Diphosphate Ribose

Substances

C9orf72 Protein
C9orf72 protein, human
DNA-Binding Proteins
Dipeptides
Poly Adenosine Diphosphate Ribose
Arginine

Abstract

Publication types

MeSH terms

Substances

Grants and funding