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

Science. 2018 Nov 2;362(6414):eaat8407. doi: 10.1126/science.aat8407.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Brain / metabolism
  • Brain / pathology
  • Cell Death
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Enzyme Activation
  • Gene Knockout Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Poly Adenosine Diphosphate Ribose / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Recombinant Proteins
  • Snca protein, mouse
  • alpha-Synuclein
  • veliparib
  • Poly Adenosine Diphosphate Ribose
  • Nitric Oxide
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1