Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis
Abstract
Parkinson's disease (PD) is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination of genetic and environmental factors contributes to such a specific loss. Among the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3 ligase, appears to be the most prevalent genetic factor in PD. Although a variety of substrates have been identified for parkin, none of them is selectively expressed in nigral DA neurons. It remains unclear how accumulation of these substrates in the absence of functional parkin may cause the selective death of DA neurons in SNpc. Here, we show that overexpression of parkin protected human DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA, but not by H(2)O(2) or rotenone. Parkin significantly attenuated dopamine-induced activation of c-Jun N-terminal kinase (JNK) and caspase-3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting DA uptake through dopamine transporter or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. Furthermore, PD-linked mutations of parkin significantly abrogated the protective effect of wild-type parkin, as well as its ability to suppress ROS and protein carbonylation. These results suggest that parkin protects against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the JNK/caspase pathway. This protective function of parkin, which is greatly attenuated by its PD-linked mutations, may be uniquely important for the survival of DA neurons, as they are constantly threatened by oxyradicals produced during dopamine oxidation.
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SH-SY5Y cell line with overexpressing wild-type and mutant Parkin exhibits decreased levels of ROS and resistance to apoptosis induced by 6-hydroxydopamine.
“This cell line with overexpressing wild-type and mutant Parkin exhibits decreased levels of ROS and resistance to apoptosis induced by 6-hydroxydopamine (Jiang et al. 2004).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Jiang et al. 2004
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- Authors
- Jiang, H., Ren, Y., Zhao, J., & Feng, J.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Jiang, Houbo
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-06-15
- Volume
- 13
- Issue
- 16
- Pages
- 1745-1754
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2158511243
- Cited by
- 239
- References
- 37
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 5 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 11 · 2015: 13 · 2014: 14 · 2013: 18 · 2012: 11
- FWCI
- 11.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS041722, NS41722)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- Parkin, Parkinson's disease, dopaminergic neurons, dopamine toxicity, apoptosis, oxidative stress, reactive oxygen species, protein carbonylation, JNK, caspase-3, dopamine transporter, parkin mutations, SH-SY5Y cells, substantia nigra pars compacta, neuroprotection
- MeSH terms
- Dopamine, Enzyme Activation, Humans, Hydrogen Peroxide, Mutation, Neurons, Parkinson Disease, Rotenone, Tumor Cells, Cultured, Blotting, Western, Gene Expression, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Caspases, In Situ Nick-End Labeling, Ubiquitin-Protein Ligases, JNK Mitogen-Activated Protein Kinases, Caspase 3
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