Could a loss of α‐synuclein function put dopaminergic neurons at risk?
Abstract
The α‐synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of α‐synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Soluble α‐synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by α‐synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional α‐synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal α‐synuclein function may contribute to the dopamine‐related loss of substantia nigra neurons during Parkinson's disease pathogenesis.
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Aggregation of α-synuclein potentiates TH phosphorylation and reduces total TH protein.
“Such aggregation of α-synuclein presumably potentiates TH phosphorylation and reduces total TH protein [116,122,123].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [122]
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-Synuclein in Parkinson's Disease
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“α-Synuclein (α-Syn), a protein highly enriched in presynaptic terminals (Maroteaux et al., 1988), is implicated in normal brain function (George et al., 1989) as well as disease (reviewed by Perez and Hastings, 2004).”
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- Authors
- Perez, R. G., & Hastings, T. G.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Perez, Ruth G.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2004-04-27
- Volume
- 89
- Issue
- 6
- Pages
- 1318-1324
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1550083773
- Cited by
- 133
- References
- 79
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 2 · 2018: 5 · 2017: 8 · 2016: 7 · 2015: 3 · 2014: 1 · 2013: 8 · 2012: 12
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institute on Drug Abuse (DA 09601)
- National Institute of Neurological Disorders and Stroke (NS42094, R21NS045336, R01NS044076, R01NS042094, NS 44076)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, Parkinson's disease, dopaminergic neurons, substantia nigra, tyrosine hydroxylase, dopamine synthesis, dopamine transport, dopamine storage, alpha-synuclein aggregation, Lewy bodies, Lewy neurites, reactive oxygen species, dopamine quinone, neurotoxicity
- MeSH terms
- Animals, Disease Models, Animal, Dopamine, Drosophila, Humans, Nerve Tissue Proteins, Neurons, Parkinson Disease, Tyrosine 3-Monooxygenase, Molecular Chaperones, Synucleins, alpha-Synuclein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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