Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism
Open accessAbstract
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson’s disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson’s disease.
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PARP1 activation is associated with Alzheimer disease and Parkinson disease pathogenesis.
“PARP1 activation is also associated with Alzheimer disease170,171 and Parkinson disease172,173 pathogenesis.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [173]
In vivo studies using various Alzheimer disease and Parkinson disease models have shown that loss of PARP1 protects from brain dysfunctions and cognitive decline.
“In vivo studies using various Alzheimer disease and Parkinson disease models have shown that loss of PARP1 protects from brain dysfunctions and cognitive decline170–174.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [173]
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“Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL, Dawson TM. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6- tetrahydropyridine (MPTP)-induced parkinsonism.”
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- Authors
- Mandir, A. S., Przedborski, S., Jackson-Lewis, V., Wang, Z.-Q., Simbulan-Rosenthal, C. M., Smulson, M. E., Hoffman, B. E., Guastella, D. B., Dawson, V. L., & Dawson, T. M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-05-11
- Volume
- 96
- Issue
- 10
- Pages
- 5774-5779
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC21936
- OpenAlex
- W2004698905
- Cited by
- 382
- References
- 58
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 10 · 2022: 10 · 2021: 14 · 2020: 12 · 2019: 8 · 2018: 11 · 2017: 14 · 2016: 9 · 2015: 11 · 2014: 10 · 2013: 9 · 2012: 16
- FWCI
- 17.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Parkinson's Disease Foundation
- American Parkinson Disease Association
- Johns Hopkins University
- National Alliance for Research on Schizophrenia and Depression
- Parkinson's Foundation
- National Institutes of Health (5r29ns037345-05, 5k08ns002035-05)
- U.S. Air Force
- U.S. Public Health Service
- National Cancer Institute (P01CA074175)
- National Institute of Neurological Disorders and Stroke (NS 38586, R01NS038586, NS37345, P50NS038377, NS 1KO8NS02035-01)
- Air Force Office of Scientific Research
- U.S. Army Medical Research and Development Command
- 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 › Oncology › PARP inhibition in cancer therapy
- Keywords
- poly(ADP-ribose) polymerase, MPTP, parkinsonism, Parkinson's disease, neurotoxicity, nitric oxide, DNA damage, poly(ADP-ribosyl)ation, substantia nigra, dopaminergic neurons, PARP inhibitors, neuroprotection
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Animals, DNA Damage, Enzyme Activation, Immunohistochemistry, Monoamine Oxidase, Nuclear Proteins, Parkinson Disease, Secondary, Poly(ADP-ribose) Polymerases, Proteins, Substantia Nigra, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-Methyl-4-phenylpyridinium, Mice, Knockout, Nitric Oxide Synthase, Mice
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