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

Research output: Contribution to journalArticle

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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Synucleins
Poly Adenosine Diphosphate Ribose
Parkinson Disease
Adenosine
Poisons
Dopaminergic Neurons
Cerebrospinal Fluid
Cell Death
Brain

ASJC Scopus subject areas

  • General

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Poly(ADP-ribose) drives pathologic a-synuclein neurodegeneration in Parkinson’s disease. / Kam, Tae-In; Mao, Xiaobo; Park, Hyejin; Chou, Shih Ching; Karuppagounder, Senthilkumar; Umanah, George; Yun, Seung Pil; Brahmachari, Saurav; Panicker, Nikhil; Chen, Rong; Andrabi, Shaida A.; Qi, Chen; Poirier, Guy G.; Pletnikova, Olga; Troncoso, Juan C; Bekris, Lynn M.; Leverenz, James B.; Pantelyat, Alexander; Ko, Hanseok Seok; Rosenthal, Liana Isa Shapiro; Dawson, Ted M; Dawson, Valina.

In: Science, Vol. 362, No. 6414, eaat8407, 02.11.2018.

Research output: Contribution to journalArticle

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AU - Mao, Xiaobo

AU - Park, Hyejin

AU - Chou, Shih Ching

AU - Karuppagounder, Senthilkumar

AU - Umanah, George

AU - Yun, Seung Pil

AU - Brahmachari, Saurav

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AU - Chen, Rong

AU - Andrabi, Shaida A.

AU - Qi, Chen

AU - Poirier, Guy G.

AU - Pletnikova, Olga

AU - Troncoso, Juan C

AU - Bekris, Lynn M.

AU - Leverenz, James B.

AU - Pantelyat, Alexander

AU - Ko, Hanseok Seok

AU - Rosenthal, Liana Isa Shapiro

AU - Dawson, Ted M

AU - Dawson, Valina

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