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Mechanisms of Dopamine Oxidation and Parkinson’s Disease

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Handbook of Neurotoxicity

Abstract

Dopamine’s ability to oxidize to aminochrome explains why this molecule may be a neurotoxic compound that induces toxicity in both cell lines and animal models. Spontaneous dopamine oxidation is prevented by vesicular monoaminergic transporter-2 (VMAT-2) that takes up dopamine into the monoaminergic synaptic vesicles where the low pH prevents dopamine oxidation. Dopamine in the cytosol can also be degraded by monoamine oxidase (MAO) and catechol ortho-methyl transferase (COMT) soluble isoform. However, under certain unknown conditions dopamine oxidize to aminochrome, the precursor of neuromelanin, pigment found in the human substantia nigra. Aminochrome participates in two neurotoxic reactions: (i) the one-electron reduction of aminochrome, which is catalyzed by flavoenzymes that use NADH or NADPH as electron donors. This reaction produces leukoaminochrome-o-semiquinone radical, which is extremely reactive with oxygen that autoxidizes depleting both NADH and O2 required for ATP synthesis; and (ii) aminochrome forms adducts with proteins such as alpha synuclein. In addition, aminochrome inactivates mitochondrial complex I of electron transport chain, vacuolar H-type ATPase, actin, and α- and β-tubulin disrupting the cytoskeleton network. Aminochrome is also able to participate in three neuroprotective reactions: (i) polymerization to neuromelanin; (ii) aminochrome two-electron reduction to leukoaminochrome catalyzed by DT-diaphorase; and (iii) glutathione conjugation of aminochrome catalyzed by glutathione S-transferase M2-2. Aminochrome’s role in the degeneration of dopaminergic neurons in Parkinson’s disease is discussed. Aminochrome may induce the focal neurodegeneration of dopaminergic neurons through mechanisms involving cytoskeleton dysfunction, mitochondrial dysfunction, protein aggregation, oxidative stress, neuroinflammation, endoplasmic reticulum stress, and protein degradation dysfunction.

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Abbreviations

AADC:

Aromatic amino acid decarboxylase

COMT:

Catechol ortho-methyltransferase

GST M2-2:

Glutathione S-transferase M2-2

L-dopa:

l-dihydroxyphenylanaline

MAO:

Monoamine oxidases

TH:

Tyrosine hydroxylase

VMAT-2:

Vesicular monoaminergic transporter-2

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Acknowledgments

Supported by FONDECYT 1100165, 1170033, 1120337 and UST N° O000034304, O000022543.

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Authors and Affiliations

  1. Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile

    Juan Segura-Aguilar

  2. Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Santiago, Chile

    Irmgard Paris

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  1. Juan Segura-Aguilar
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Correspondence to Juan Segura-Aguilar .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Segura-Aguilar, J., Paris, I. (2022). Mechanisms of Dopamine Oxidation and Parkinson’s Disease. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_16-1

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