Role of dopamine in the pathophysiology of Parkinson's disease

Abstract

A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.

Keywords: 3,4-Dihydroxyphenylacetaldehyde; Dopamine; Dopamine quinones; Neurodegeneration; Parkinson's disease; Pathogenesis; Reactive oxygen species; Therapeutic strategies.

Fig. 1

DA metabolic pathways. DA is unstable and can undergo oxidation to produce reactive DOQ and ROS. The reaction can be reversed under sufficient ambient reductive force. The reactive DOQ can covalently conjugate with protein residues via MA reaction to form DOQ-protein adducts. DOQ can further be oxidized to generate ROS and AM, a cyclized DAQ. AM can also conjugate with protein residues to form AM-protein adducts via MA reaction or undergo internal rearrangement to form 5,6-dihydroxyindole, which can further polymerize to form melanin. Alternatively, DA can be catalyzed by COMT to form non-toxic 3-MT and finally HVA. DA can also be catalyzed by MAO to form reactive DOPAL and ROS. DOPAL can be catalyzed by ALDH to form non-toxic DOPAC and generate HVA under the catalysis of COMT. DOPAL can also be reduced by ALR/AR to form inactivate DOPAE. However, DOPAL is reactive and can conjugate with protein lysine residues to form DOPAL-protein adducts via SB reaction. DOPAL can be further oxidized to generate reactive ROS and DPQ, while DPQ can conjugate with protein residues via MA reaction to form DPQ-protein adducts. ALDH  aldehyde dehydrogenase, AM aminochrome, COMT catechol-o-methyltransferase, DA dopamine, DOPAL 3,4-dihydroxyphenylacetaldehyde, DOQ DA-o-quinone, DPQ DOPAL-quinone, HVA homovanillic acid, 3-MT 3-methoxytyramine

Fig. 2

Hypothetical conjugations of DAQs and DOPAL with protein residues, leading to protein modifications and cross-linking. a–c DAQ or DOPAL conjugations to peptide A. a SB adductive reaction of DOPAL with lysine; b MA adductive reaction of DOQ with cysteine; c MA adductive reaction of DOQ with tyrosine residue. d–i DAQ or DOPAL conjugation and cross-linking between peptides A and B. d MA adductive reactions of DOQ with two cysteine residues; e MA and SB adductive reactions of DPQ with cysteine and lysine residues, respectively; f MA adductive reactions of DOQ with tyrosine and cysteine residues; g MA adductive reactions of DOQ with two tyrosine residues; h MA and SB adductive reactions of DPQ with tyrosine and lysine residues, respectively; i MA and SB adductive reactions of DPQ with two lysine residues. j–o DAQ or DOPAL conjugations and cross-linking between peptides B and C. j MA adductive reactions of AM with two cysteine residues; k MA adductive reactions of AM with cysteine and tyrosine residues; l MA adductive reactions of AM with two tyrosine residues; m MA adductive reactions of DPQ with two cysteine residues; n MA adductive reactions of DPQ with cysteine and tyrosine residues; o MA adductive reactions of DPQ with two tyrosine residues; p–s Conjugations to peptide C. p MA adductive reaction of AM with cysteine residue; q MA adductive reaction of AM with tyrosine residue; r MA adductive reaction of DPQ with cysteine residue; s MA adductive reaction of DPQ with tyrosine residue

Fig. 3

LRRK2-PINK1 kinase pair balance in modulation of TH-DA pathway, significant to PD pathogenesis and therapy. LRRK2 and PINK1 form a functional kinase pair balance to regulate TH expression and DA production in DA neurons. a LRRK2 enhances TH expression and DA synthesis, while PINK1 inhibits TH expression and DA production. LRRK2 and PINK1 can promote proteasome degradation of each other, leading to a function l kinase balance in steady state. Under physiological conditions, the moderate DA level in brains will cause mild stress to DA neurons by reactive ROS, DAQs and DOPAL generated from DA oxidation and MAO catalyzed DA metabolism. DA neurons can survive and be healthy. b However when LRRK2 is mutated, LRRK2 kinase activity can be increased to up-regulate TH and DA levels. The increased LRRK2 kinase activity will also promote PINK1 degradation to inhibit PINK1 function. This will lead to an imbalance between LRRK2 and PINK1 kinase pair, contributing to increased TH and DA levels, elevated generation of toxic DA by-products and DA neuron vulnerability. c Vice versa, under PINK1 mutations, the PINK1 kinase activity can be impaired, which will also disturb the LRRK2-PINK1 kinase balance, leading to deregulated TH-DA pathway, enhanced generation of toxic DA by-products, and DA neuron vulnerability