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Science. 2018 Nov 2;362(6414). pii: eaat8407. doi: 10.1126/science.aat8407.

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

Kam TI1,2,3, Mao X1,2,3, Park H1,2,3, Chou SC1,4, Karuppagounder SS1,2,3, Umanah GE1,2, Yun SP1,2,3, Brahmachari S1,2,3, Panicker N1,2,3, Chen R1,2,3, Andrabi SA1,2, Qi C1,2,5, Poirier GG6, Pletnikova O7, Troncoso JC2,7, Bekris LM8, Leverenz JB9, Pantelyat A2, Ko HS1,2,3, Rosenthal LS2, Dawson TM10,2,3,4,11, Dawson VL10,2,3,11,12.

Author information

1
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
4
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
6
Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.
7
Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
9
Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA.
10
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu vdawson1@jhmi.edu.
11
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-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.

PMID:
30385548
DOI:
10.1126/science.aat8407

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