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

Kam Tae-In TI Mao Xiaobo X Park Hyejin H Chou Shih-Ching SC Karuppagounder Senthilkumar S SS Umanah George Essien GE Yun Seung Pil SP Brahmachari Saurav S Panicker Nikhil N Chen Rong R Andrabi Shaida A SA Qi Chen C Poirier Guy G GG Pletnikova Olga O Troncoso Juan C JC Bekris Lynn M LM Leverenz James B JB Pantelyat Alexander A Ko Han Seok HS Rosenthal Liana S LS Dawson Ted M TM Dawson Valina L VL

Science (New York, N.Y.) 20181101 6414

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]

PMID: 30385548

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Project description:Background/objectiveDespite multiple attempts, no surrogate biomarker of Parkinson disease (PD) has been definitively identified. Alternatively, identifying a non-invasive biomarker is crucial to understanding the natural history, severity, and progression of PD and to guide future therapeutic trials. Recent work highlighted alpha synuclein-containing extracellular vesicles and Poly (ADP-ribose) polymerase (PARP-1) activity as drivers of PD pathogenesis and putative PD biomarkers. This exploratory study evaluated the role of alpha-synuclein-positive extracellular vesicles and PARP-1 activity in the plasma of PD patients as non-invasive markers of the disease's severity and progression.MethodsWe collected plasma of 57 PD patients (discovery cohort 20, replication cohort 37) and compared it with 20 unaffected individuals, 20 individuals with clinically diagnosed Alzheimer's disease, and 20 individuals with dementia with Lewy bodies. We analyzed alpha-synuclein-positive extracellular vesicles from platelet-free plasma by nanoscale flow cytometry and blood concentrations of poly ADP-ribose using sandwich ELISA kits.ResultsMedian concentration of α-synuclein extracellular vesicles was significantly higher in PD patients compared to the other groups (Kruskal-Wallis, p < .0001). In the discovery cohort, patients with higher α-synuclein extracellular vesicles had a higher Unified Parkinson Disease Rating Scale score (UPDRS III median = 22 vs. 5, p = 0.045). Seven out of 20 patients (35%) showed detectable PAR levels, with positive patients showing significantly higher levels of α-synuclein extracellular vesicles. In the replication cohort, we did not observe a significant difference in the PAR-positive cases in relationship with UPDRS III.ConclusionsNon-invasive determination of α-synuclein-positive extracellular vesicles may provide a potential non-invasive marker of PD disease severity, and longitudinal studies are needed to evaluate the role of α-synuclein-positive extracellular vesicles as a marker of disease progression.

Dataset Information

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

Publications

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

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