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.
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