Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | eaat8407 |
| Journal | Science |
| Volume | 362 |
| Issue number | 6414 |
| DOIs | |
| State | Published - Nov 2 2018 |
Fingerprint
ASJC Scopus subject areas
- General
Cite this
Poly(ADP-ribose) drives pathologic a-synuclein neurodegeneration in Parkinson’s disease. / Kam, Tae-In; Mao, Xiaobo; Park, Hyejin; Chou, Shih Ching; Karuppagounder, Senthilkumar; Umanah, George; Yun, Seung Pil; Brahmachari, Saurav; Panicker, Nikhil; Chen, Rong; Andrabi, Shaida A.; Qi, Chen; Poirier, Guy G.; Pletnikova, Olga; Troncoso, Juan C; Bekris, Lynn M.; Leverenz, James B.; Pantelyat, Alexander; Ko, Hanseok Seok; Rosenthal, Liana Isa Shapiro; Dawson, Ted M; Dawson, Valina.
In: Science, Vol. 362, No. 6414, eaat8407, 02.11.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Poly(ADP-ribose) drives pathologic a-synuclein neurodegeneration in Parkinson’s disease
AU - Kam, Tae-In
AU - Mao, Xiaobo
AU - Park, Hyejin
AU - Chou, Shih Ching
AU - Karuppagounder, Senthilkumar
AU - Umanah, George
AU - Yun, Seung Pil
AU - Brahmachari, Saurav
AU - Panicker, Nikhil
AU - Chen, Rong
AU - Andrabi, Shaida A.
AU - Qi, Chen
AU - Poirier, Guy G.
AU - Pletnikova, Olga
AU - Troncoso, Juan C
AU - Bekris, Lynn M.
AU - Leverenz, James B.
AU - Pantelyat, Alexander
AU - Ko, Hanseok Seok
AU - Rosenthal, Liana Isa Shapiro
AU - Dawson, Ted M
AU - Dawson, Valina
PY - 2018/11/2
Y1 - 2018/11/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055900192&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055900192&partnerID=8YFLogxK
U2 - 10.1126/science.aat8407
DO - 10.1126/science.aat8407
M3 - Article
C2 - 30385548
AN - SCOPUS:85055900192
VL - 362
JO - Science
JF - Science
SN - 0036-8075
IS - 6414
M1 - eaat8407
ER -