| First Author | Kam TI | Year | 2018 |
| Journal | Science | Volume | 362 |
| Issue | 6414 | PubMed ID | 30385548 |
| Mgi Jnum | J:266991 | Mgi Id | MGI:6257404 |
| Doi | 10.1126/science.aat8407 | Citation | Kam TI, et al. (2018) Poly(ADP-ribose) drives pathologic alpha-synuclein neurodegeneration in Parkinson's disease. Science 362(6414) |
| abstractText | 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. |
