Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

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  • Tae-In Kam
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Xiaobo Mao
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Hyejin Park
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Shih-Ching Chou
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Senthilkumar S. Karuppagounder
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • George Essien Umanah
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Seung Pil Yun
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Saurav Brahmachari
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Nikhil Panicker
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Rong Chen
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Shaida A. Andrabi
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Chen Qi
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Guy G. Poirier
    Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.
  • Olga Pletnikova
    Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Juan C. Troncoso
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Lynn M. Bekris
    Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
  • James B. Leverenz
    Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA.
  • Alexander Pantelyat
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Han Seok Ko
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Liana S. Rosenthal
    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Ted M. Dawson
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Valina L. Dawson
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Description

<jats:title>PAR promotes α-synuclein toxicity</jats:title> <jats:p> How pathologic α-synuclein (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam <jats:italic>et al.</jats:italic> studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see the Perspective by Brundin and Wyse). They found that pathologic α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) and inhibition of PARP or knockout of PARP-1 protected mice from pathology. The generation of PAR by α-syn PFF–induced PARP-1 activation converted α-syn PFF to a strain that was 25-fold more toxic, termed PAR–α-syn PFF. An increase of PAR in the cerebrospinal fluid and evidence of PARP activation in the substantia nigra of PD patients indicates that PARP activation contributes to the pathogenesis of PD through parthanatos and conversion of α-syn to a more toxic strain. </jats:p> <jats:p> <jats:italic>Science</jats:italic> , this issue p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" related-article-type="in-this-issue" xlink:href="10.1126/science.aat8407">eaat8407</jats:related-article> ; see also p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6414" page="521" related-article-type="in-this-issue" vol="362" xlink:href="10.1126/science.aav3986">521</jats:related-article> </jats:p>

Journal

  • Science

    Science 362 (6414), 6414-, 2018-11-02

    American Association for the Advancement of Science (AAAS)

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