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

Tae-In Kam, Xiaobo Mao, Hyejin Park, Shih Ching Chou, Senthilkumar Karuppagounder, George Umanah, Seung Pil Yun, Saurav Brahmachari, Nikhil Panicker, Rong Chen, Shaida A. Andrabi, Chen Qi, Guy G. Poirier, Olga Pletnikova, Juan C Troncoso, Lynn M. Bekris, James B. Leverenz, Alexander Pantelyat, Hanseok Seok Ko, Liana Isa Shapiro RosenthalTed M Dawson, Valina Dawson

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Abstract

The pathologic accumulation and aggregation of a-synuclein (a-syn) underlies Parkinson’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.

Original languageEnglish (US)
Article numbereaat8407
JournalScience
Volume362
Issue number6414
DOIs
StatePublished - Nov 2 2018

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