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Cited by 56Parkinson's Disease Mechanisms and TreatmentsNeurotransmitter Receptor Influence on BehaviorRedox biology and oxidative stress

Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo

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Vecchio, Laura M., Sullivan, Patricia, Dunn, Amy R., Bermejo, Marie Kristel, Fu, Rong, Masoud, Shababa T., Gregersen, Emil, Urs, Nikhil M. +6 more·2021·Journal of Neurochemistry
DOI 10.1111/jnc.15432PMC PMC8376767
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Abstract

In Parkinson's disease, dopamine‐containing nigrostriatal neurons undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in dopamine biosynthesis. TH increases in vitro formation of reactive oxygen species, and previous animal studies have reported links between cytosolic dopamine build‐up and oxidative stress. To examine effects of increased TH activity in catecholaminergic neurons in vivo, we generated TH‐over‐expressing mice (TH‐HI) using a BAC‐transgenic approach that results in over‐expression of TH with endogenous patterns of expression. The transgenic mice were characterized by western blot, qPCR, and immunohistochemistry. Tissue contents of dopamine, its metabolites, and markers of oxidative stress were evaluated. TH‐HI mice had a 3‐fold increase in total and phosphorylated TH levels and an increased rate of dopamine synthesis. Coincident with elevated dopamine turnover, TH‐HI mice showed increased striatal production of H 2 O 2 and reduced glutathione levels. In addition, TH‐HI mice had elevated striatal levels of the neurotoxic dopamine metabolites 3,4‐dihydroxyphenylacetaldehyde and 5‐S‐cysteinyl‐dopamine and were more susceptible than wild‐type mice to the effects of amphetamine and methamphetamine. These results demonstrate that increased TH alone is sufficient to produce oxidative stress in vivo, build up autotoxic dopamine metabolites, and augment toxicity. image

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  • Sustained increases in dopamine release within the striatum could result in the toxic accumulation of hyperoxidative dopamine metabolites such as reactive oxygen species and dopamine quinones, causing a dying back of SNc DA axons in the striatum and thereby leading to the accelerated loss of SNc DA neurons.

    “Together, these reports suggest that sustained increases in dopamine release within the striatum could result in the toxic accumulation of hyperoxidative dopamine metabolites such as reactive oxygen species and dopamine quinones, causing a dying back of SNc DA axons in the striatum and thereby leading to the accelerated loss of SNc DA neurons.”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Vecchio et al. 2021

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  • Overexpression of TH in mice results in hyperoxidative stress, which can eventually lead to accelerated SNc DA neuron loss.

    “overexpression of TH in mice, which is the rate limiting enzyme for dopamine synthesis results in hyperoxidative stress, which can eventually lead to accelerated SNc DA neuron loss (Vecchio et al. 2021).”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Vecchio et al. 2021

    The Results and Discussion report that TH-overexpressing mice developed markers of oxidative stress, including elevated striatal H2O2 and reduced glutathione. The Discussion raises dopaminergic cell degeneration as a possible pathway for future study, but does not show that these mice undergo accelerated SNc dopamine-neuron loss. (LLM, conf=0.86)

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Sorted by citations

Authors
Vecchio, L. M., Sullivan, P., Dunn, A. R., Bermejo, M. K., Fu, R., Masoud, S. T., Gregersen, E., Urs, N. M., Nazari, R., Jensen, P. H., Ramsey, A., Goldstein, D. S., Miller, G. W., & Salahpour, A.
Affiliations
  • University of Toronto (CA)
  • National Institutes of Health (US)
  • Jackson Laboratory (US)
  • Emory University (US)
  • Aarhus University (DK)
  • University of Florida Health (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Salahpour, Ali
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2021-06-12
Volume
158
Issue
4
Pages
960-979
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.15432
PMC
PMC8376767
OpenAlex
W3163373675
Cited by
56
References
9
Citations by year
2026: 15 · 2025: 13 · 2024: 4 · 2023: 12 · 2022: 8 · 2021: 4
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by-nc)
Funders
  • Canadian Institutes of Health Research (210296, 258294)
  • Lundbeckfonden (R223‐2015‐4222, R248‐2016‐2518)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
tyrosine hydroxylase, Parkinson's disease, oxidative stress, dopamine metabolism, dopamine metabolites, DOPAL, amphetamine sensitivity, methamphetamine neurotoxicity, striatum, glutathione depletion, hydrogen peroxide, catecholaminergic neurons, transgenic mice, dopamine synthesis
MeSH terms
Amphetamine, Central Nervous System Stimulants, Animals, Catecholamines, Dopamine, Female, Glutathione, Humans, Hydrogen Peroxide, Male, Mice, Transgenic, Neurons, Tyrosine 3-Monooxygenase, 3,4-Dihydroxyphenylacetic Acid, Oxidative Stress, Gene Dosage, Mice

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