| Literature DB >> 30385548 |
Tae-In Kam1,2,3, Xiaobo Mao1,2,3, Hyejin Park1,2,3, Shih-Ching Chou1,4, Senthilkumar S Karuppagounder1,2,3, George Essien Umanah1,2, Seung Pil Yun1,2,3, Saurav Brahmachari1,2,3, Nikhil Panicker1,2,3, Rong Chen1,2,3, Shaida A Andrabi1,2, Chen Qi1,2,5, Guy G Poirier6, Olga Pletnikova7, Juan C Troncoso2,7, Lynn M Bekris8, James B Leverenz9, Alexander Pantelyat2, Han Seok Ko1,2,3, Liana S Rosenthal2, Ted M Dawson10,2,3,4,11, Valina L Dawson10,2,3,11,12.
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.Entities:
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Year: 2018 PMID： 30385548 PMCID： PMC6431793 DOI： 10.1126/science.aat8407
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728