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Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins.
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; Guo, Lin; Dawson, Ted M; Dawson, Valina L; Leung, Anthony K L; Lloyd, Thomas E; Gendron, Tania F; Rothstein, Jeffrey D; Zhang, Ke.
Afiliación
  • Gao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Mewborne QT; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Girdhar A; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Sheth U; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Coyne AN; Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Punathil R; Brain Science Institute, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Kang BG; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Dasovich M; Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Veire A; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • DeJesus Hernandez M; Department of Chemistry, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Liu S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Shi Z; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Dafinca R; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Fouquerel E; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
  • Talbot K; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
  • Kam TI; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Zhang YJ; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
  • Dickson D; Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • van Blitterswijk M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Guo L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Dawson TM; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA.
  • Dawson VL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Leung AKL; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • Lloyd TE; Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Gendron TF; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Rothstein JD; Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
  • Zhang K; Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
Sci Transl Med ; 14(662): eabq3215, 2022 09 14.
Article en En | MEDLINE | ID: mdl-36103513
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Demencia Frontotemporal Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos