Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease
Open accessAbstract
PAR promotes α-synuclein toxicity: How pathologic α-synuclein (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see the Perspective by Brundin and Wyse). They found that pathologic α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) and inhibition of PARP or knockout of PARP-1 protected mice from pathology. The generation of PAR by α-syn PFF–induced PARP-1 activation converted α-syn PFF to a strain that was 25-fold more toxic, termed PAR–α-syn PFF. An increase of PAR in the cerebrospinal fluid and evidence of PARP activation in the substantia nigra of PD patients indicates that PARP activation contributes to the pathogenesis of PD through parthanatos and conversion of α-syn to a more toxic strain. Science , this issue p. eaat8407 ; see also p. 521
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Parkinson's disease is a progressive fatal neurological disorder of aging that profoundly impairs control of body movements due to loss of dopaminergic neurons in the substantia nigra, which exhibit abnormal accumulation of α-synuclein fibrils in their cell body and neurites.
“PD is a progressive fatal neurological disorder of aging that profoundly impairs one’s ability to control body movements as the result of loss of dopaminergic neurons in the substantia nigra, which exhibit abnormal accumulation of α-synuclein fibrils in their cell body and neurites (Kam et al., 2018; Spillantini et al., 1997).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Kam et al., 2018
Oxidative damage-induced poly(ADP-ribose) mediates α-synuclein aggregation and consequent neurodegeneration in PD.
“oxidative damage‐induced poly(ADP‐ribose) mediates α‐synuclein aggregation and consequent neurodegeneration in PD (Kam et al, 2018)”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Kam et al, 2018
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- Authors
- Kam, T.-I., Mao, X., Park, H., Chou, S.-C., Karuppagounder, S. S., Umanah, G. E., Yun, S. P., Brahmachari, S., Panicker, N., Chen, R., Andrabi, S. A., Qi, C., Poirier, G. G., Pletnikova, O., Troncoso, J. C., Bekris, L. M., Leverenz, J. B., Pantelyat, A., Ko, H. S., Rosenthal, L. S., Dawson, T. M., & Dawson, V. L.
- Affiliations
- Johns Hopkins University (US)
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Centre hospitalier de l'Université Laval (CA)
- Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Cleveland Clinic (US)
- Corresponding author
- Kam, Tae-In
- Mao, Xiaobo
- Park, Hyejin
- Dawson, Ted M.
- Dawson, Valina L.
- ORCID
- Kam, Tae-In
- Mao, Xiaobo
- Park, Hyejin
- Karuppagounder, Senthilkumar S.
- Umanah, George Essien
- Yun, Seung Pil
- Brahmachari, Saurav
- Panicker, Nikhil
- Chen, Rong
- Andrabi, Shaida A.
- Qi, Chen
- Poirier, Guy G.
- Troncoso, Juan C.
- Bekris, Lynn M.
- Leverenz, James B.
- Pantelyat, Alexander
- Ko, Han Seok
- Rosenthal, Liana S.
- Dawson, Ted M.
- Dawson, Valina L.
- Venue
- Science
- Published
- 2018-11-02
- Volume
- 362
- Issue
- 6414
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6431793
- OpenAlex
- W2898743739
- Cited by
- 476
- References
- 30
- Citations by year
- 2026: 46 · 2025: 60 · 2024: 67 · 2023: 59 · 2022: 59 · 2021: 74 · 2020: 55 · 2019: 51 · 2018: 3 · 2017: 1 · 2013: 1
- FWCI
- 31.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P50NS38377, R37NS067525, NS082205, U01NS082133, U01NS097049, U01NS100610, R01NS086953)
- Jane and Lee Seidman Fund (N/A)
- Adrienne Helis Malvin Medical Research Foundation (M-2016)
- NIH/National Institute on Aging grant (1K01AG056841-01)
- American Parkinson Disease Association (APDA) Research Grant
- JPB Foundation
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Parkinson's disease, alpha-synuclein aggregation, poly(ADP-ribose), PARP1, parthanatos, neurodegeneration, PARP inhibitors, dopaminergic neurons, cerebrospinal fluid biomarkers, feed-forward loop, disease-modifying therapy
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Animals, Benzimidazoles, Brain, Enzyme Activation, Mice, Inbred C57BL, Nitric Oxide, Parkinson Disease, Poly Adenosine Diphosphate Ribose, Recombinant Proteins, Cell Death, Mice, Knockout, Mice, alpha-Synuclein, Gene Knockout Techniques, Dopaminergic Neurons
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