@article{78d8e3a253f544a9a27f35fa22d9afd8,
title = "Poly(ADP-ribose) drives pathologic a-synuclein neurodegeneration in Parkinson{\textquoteright}s disease",
abstract = "The pathologic accumulation and aggregation of a-synuclein (a-syn) underlies Parkinson{\textquoteright}s disease (PD). The molecular mechanisms by which pathologic a-syn causes neurodegeneration in PD are not known. Here, we found that pathologic a-syn activates poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic a-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic a-syn toxicity. In a feed-forward loop, PAR converted pathologic a-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.",
author = "Kam, {Tae In} and Xiaobo Mao and Hyejin Park and Chou, {Shih Ching} and Karuppagounder, {Senthilkumar S.} and Umanah, {George Essien} and Yun, {Seung Pil} and Saurav Brahmachari and Nikhil Panicker and Rong Chen and Andrabi, {Shaida A.} and Chen Qi and Poirier, {Guy G.} and Olga Pletnikova and Troncoso, {Juan C.} and Bekris, {Lynn M.} and Leverenz, {James B.} and Alexander Pantelyat and Ko, {Han Seok} and Rosenthal, {Liana S.} and Dawson, {Ted M.} and Dawson, {Valina L.}",
note = "Funding Information: We thank I.-H. Wu for graphic art assistance, H. Gu for collecting data and writing assistance, N. Yoritomo and M. Gudavalli for assistance in patient recruitment and biospecimen collection, and the patients and families that volunteer and participate in research. This work was supported by grants from the NIH/NINDS (P50NS38377, R37NS067525, NS082205, U01NS082133, and U01NS097049) and the JPB Foundation and by UO1 NS100610 and the Jane and Lee Seidman Fund to J.B.L. We acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation{\textquoteright}s Parkinson{\textquoteright}s Disease Programs M-2016. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. Funding Information: 1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. 4Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 5Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. 6Centre de recherche du CHU de Qu{\'e}bec-Pavillon CHUL, Facult{\'e} de M{\'e}decine, Universit{\'e} Laval, Qu{\'e}bec G1V 4G2, Canada. 7Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 8Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. 9Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA. 10Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 11Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. *These authors contributed equally to this work. †Present address: Departmental of Pharmacology and Toxicology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-6810, USA. Publisher Copyright: {\textcopyright} 2017 The Authors.",
year = "2018",
month = nov,
day = "2",
doi = "10.1126/science.aat8407",
language = "English (US)",
volume = "362",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6414",
}