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

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The pathologic accumulation and aggregation of alpha-synuclein (alpha-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic alpha-syn causes neurodegeneration in PD are not known. Here, we found that pathologic alpha-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic alpha-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic alpha-syn toxicity. In a feed-forward loop, PAR converted pathologic alpha-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.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Issue Date
2018-11
Language
English
Article Type
Article
Citation

SCIENCE, v.362, no.6414

ISSN
0036-8075
DOI
10.1126/science.aat8407
URI
http://hdl.handle.net/10203/305550
Appears in Collection
BC-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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