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Cited by 106Parkinson's Disease Mechanisms and TreatmentsRedox biology and oxidative stressAntioxidant Activity and Oxidative Stress

Products of Oxidative Stress Inhibit Aldehyde Oxidation and Reduction Pathways in Dopamine Catabolism Yielding Elevated Levels of a Reactive Intermediate

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Jinsmaa, Yunden, Florang, Virginia R., Rees, Jennifer N., Anderson, David G., Strack, Stefan, Doorn, Jonathan A.·2009·Chemical Research in Toxicology
DOI 10.1021/tx800405vPMC PMC2696154
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Abstract

Dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration as observed for Parkinson's disease (PD). In addition, oxidative stress and lipid peroxidation are hypothesized culprits in PD pathogenesis. DA undergoes catabolism by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). As a minor and compensatory metabolic pathway, DOPAL can be reduced to 3,4-dihydroxyphenylethanol (DOPET) via cytosolic aldehyde or aldose reductase (AR). Previous studies have found DOPAL to be significantly more toxic to DA cells than DA and that the major lipid peroxidation products, that is, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit DOPAL oxidation via ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the toxic aldehyde intermediate. To test this hypothesis, nerve growth factor-differentiated PC6-3 cells were used as a model for DA neurons. Cell viability in the presence of 4HNE and MDA (2-100 microM) was measured by MTT assay, and it was found that only 100 microM 4HNE exhibited significant cytotoxicity. Treatment of cells with varying concentrations of 4HNE and MDA resulted in reduced DOPAC production and significant elevation of DOPAL levels, suggesting inhibition of ALDH. In cells treated with 4HNE that exhibited elevated DOPAL, there was a significant increase in DOPET. However, elevated DOPET was not observed for the cells treated with MDA, suggesting MDA to be an inhibitor of AR. Using isolated cytosolic AR, it was found that MDA but not 4HNE inhibited reductase activity toward DOPAL, surprisingly. These data demonstrate that the oxidative stress products 4HNE and MDA inhibit the aldehyde biotransformation step of DA catabolism yielding elevated levels of the endogenous neurotoxin DOPAL, which may link oxidative stress to selective neurodegeneration as seen in PD.

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  • The aldehyde may target and modify proteins important for dopamine neuron homeostasis, including α-synuclein.

    “The aldehyde may target and modify proteins important for dopamine neuron homeostasis including -synuclein (α-syn) (Jinsmaa et al, 2009).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Jinsmaa et al, 2009

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  • Iron, Oxidative Stress and Health

    Udipi, S., Ghugre, P., & Gokhale, C. (2012) · Oxidative Stress - Molecular Mechanisms and Biological Effects · doi:10.5772/34975 · Cited by 17 · see citing works

    “The aldehyde may target and modify proteins important for dopamine neuron homeostasis including ┙-synuclein (α-syn) (Jinsmaa et al, 2009).”
    Background

Authors
Jinsmaa, Y., Florang, V. R., Rees, J. N., Anderson, D. G., Strack, S., & Doorn, J. A.
Affiliations
University of Iowa (US)
Corresponding author
Doorn, Jonathan A.
ORCID
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
2009-04-23
Volume
22
Issue
5
Pages
835-841
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/tx800405v
PMC
PMC2696154
OpenAlex
W2007271767
Cited by
106
References
5
Citations by year
2026: 2 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 12 · 2020: 3 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 6 · 2013: 3 · 2012: 14
FWCI
6.40
Type
journal article
Language
en
Open access
Locations
  • Chemical Research in Toxicology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (T32GM008365, T32-GM08365)
  • National Institute of Environmental Health Sciences (P30-ES-05605, R01 ES15507, K22ES012982, R01ES015507, K22 ES12982, P30ES005605)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
dopamine catabolism, DOPAL, oxidative stress, lipid peroxidation, 4-hydroxynonenal, malondialdehyde, aldehyde dehydrogenase inhibition, aldose reductase inhibition, DOPAC, Parkinson's disease, neurotoxicity, dopaminergic neurons, monoamine oxidase
MeSH terms
Aldehydes, Aldehyde Reductase, Animals, Dopamine, Malondialdehyde, Oxidation-Reduction, Phenylethyl Alcohol, 3,4-Dihydroxyphenylacetic Acid, Lipid Peroxidation, PC12 Cells, Oxidative Stress, Rats

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