Mechanisms of dopamine oxidation and parkinson's disease

Abstract

Dopamine's ability to oxidize to aminochrome explains why this molecule is both an essential neurotransmitter for movement control and a neurotoxic compound that induces toxicity and apoptosis in cell lines. Dopamine spontaneously oxidizes to aminochrome in the presence of oxygen due to the protons on the dopamine hydroxyl groups that are dissociated when dopamine is in the cytosol (pH 7.4). 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-methyltransferase (COMT) soluble isoform. However, under certain unknown conditions dopamine oxidize to aminochrome, the precursor of neuromelanin, since the neuromelanin pigment is 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 leukoami- nochrome o-semiquinone radical, which is extremely reactive with oxygen that autoxidizes, depleting both NADH and O2 required for ATP synthesis when the flavoenzymes use NADH; and (ii) aminochrome forms adducts with proteins such as alpha-synuclein-inducing and alpha-synuclein-stabilizing neurotoxic protofibrils. In addition, aminochrome inactivate parkin an E3 ubiquitin ligase of proteasomal system, complexes I and III of electron transport chain, tyrosine hydroxylase, actin, and A- and ß-tubulin. Aminochrome is also able to participate in three neuroprotective reactions such as (i) polymerization to neuromelanin, which is a pigment localized in substantia nigra and is present in normal subjects; (ii) aminochrome two-electron reduction to leukoami- nochrome catalyzed by DT-diaphorase, which prevents aminochrome neurotoxic reactions; and (iii) glutathione conjugation of aminochrome catalyzed by glutathione S-transferase M2-2. The role of aminochrome in the degeneration of dopaminergic neurons in Parkinson's disease is discussed. Aminochrome may induce the focal neurodegeneration of dopaminergic neurons through mechanisms involving mitochondrial dysfunction, protein aggregation, oxidative stress, and protein degradation dysfunction.