Uncoupling Protein-2 Is Critical for Nigral Dopamine Cell Survival in a Mouse Model of Parkinson's Disease
Open accessAbstract
Mitochondrial uncoupling proteins dissociate ATP synthesis from oxygen consumption in mitochondria and suppress free-radical production. We show that genetic manipulation of uncoupling protein-2 (UCP2) directly affects substantia nigra dopamine cell function. Overexpression of UCP2 increases mitochondrial uncoupling, whereas deletion of UCP2 reduces uncoupling in the substantia nigra-ventral tegmental area. Overexpression of UCP2 decreased reactive oxygen species (ROS) production, which was measured using dihydroethidium because it is specifically oxidized to fluorescent ethidium by the superoxide anion, whereas mice lacking UCP2 exhibited increased ROS relative to wild-type controls. Unbiased electron microscopic analysis revealed that the elevation of in situ mitochondrial ROS production in UCP2 knock-out mice was inversely correlated with mitochondria number in dopamine neurons. Lack of UCP2 increased the sensitivity of dopamine neurons to 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP), whereas UCP2 overexpression decreased MPTP-induced nigral dopamine cell loss. The present results expose the critical importance of UCP2 in normal nigral dopamine cell metabolism and offer a novel therapeutic target, UCP2, for the prevention/treatment of Parkinson's disease.
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UCP2 helps preserve dopamine neurons in a mouse model of Parkinson disease due, in part, to its ability to reduce ROS production.
“Other studies, however, suggest that UCP2 helps to preserve dopamine neurons in a mouse model of Parkinson disease due, in part, to its ability to reduce ROS production: in this model deficient mice had more ROS and increased cell loss compared to wild-type controls, whereas UCP2 overexpressing mice were more protected with less ROS and less cell death (12).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [12]
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References 32 · Cited by 199
- Authors
- Andrews, Z. B., Horvath, B., Barnstable, C. J., Elseworth, J., Yang, L., Beal, M. F., Roth, R. H., Matthews, R. T., & Horvath, T. L.
- Affiliations
- Yale University (US)
- Cornell University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-01-05
- Volume
- 25
- Issue
- 1
- Pages
- 184-191
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725213
- OpenAlex
- W2062344501
- Cited by
- 199
- References
- 32
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 13 · 2013: 9 · 2012: 22
- FWCI
- 9.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 NS)
- National Institute of Neurological Disorders and Stroke (R01NS041725, R01 NS-41725)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- UCP2, Parkinson's disease, substantia nigra, dopaminergic neurons, mitochondrial uncoupling, reactive oxygen species, superoxide, MPTP-induced neurotoxicity, UCP2 knockout mice, mitochondrial number, therapeutic target
- MeSH terms
- Uncoupling Protein 2, Animals, Cell Survival, Corpus Striatum, Disease Models, Animal, Dopamine, Humans, Immunohistochemistry, Ion Channels, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Oxygen Consumption, Substantia Nigra, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-Methyl-4-phenylpyridinium, Reactive Oxygen Species, Mice, Knockout, Parkinsonian Disorders, Mitochondrial Proteins, Membrane Transport Proteins, Mice
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