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

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

SUBMITTER: Kam TI 

PROVIDER: S-EPMC6431793 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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 toxici  ...[more]

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