Oxidative Stress and Neuroinflammation in Parkinson's Disease: The Role of Dopamine Oxidation Products

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative condition affecting more than 1% of people over 65 years old. It is characterized by the preferential degeneration of nigrostriatal dopaminergic neurons, which is responsible for the motor symptoms of PD patients. The pathogenesis of this multifactorial disorder is still elusive, hampering the discovery of therapeutic strategies able to suppress the disease's progression. While redox alterations, mitochondrial dysfunctions, and neuroinflammation are clearly involved in PD pathology, how these processes lead to the preferential degeneration of dopaminergic neurons is still an unanswered question. In this context, the presence of dopamine itself within this neuronal population could represent a crucial determinant. In the present review, an attempt is made to link the aforementioned pathways to the oxidation chemistry of dopamine, leading to the formation of free radical species, reactive quinones and toxic metabolites, and sustaining a pathological vicious cycle.

Keywords: DOPAL; Parkinson’s disease; dopamine; neuromelanin; oxidative stress; synuclein.

Figure 1

The vicious cycle in Parkinson’s disease, involving alterations in redox homeostasis, dysfunctional mitochondria, and neuroinflammation. Mitochondria are the main site of ROS production, and, at the same time, ROS may affect mitochondrial functionality. Mitochondria can stimulate neuroinflammatory responses through the release of damage-associated molecular patterns (DAMPs). Chronic activation of microglia stimulates the production of ROS through the activation of NADPH oxidase (NOX). In dopaminergic neurons, cytosolic dopamine (DA) can auto-oxidase leading to the generation of ROS and reactive quinones (DAQs), which can either react with cellular nucleophiles or aggregate into neuromelanin (NM). The release of NM from dying neurons can fuel neuroinflammatory processes by activating microglia. Alternatively, cytosolic DA can be metabolized at the mitochondrial level into the very reactive molecule dihydroxyphenylacetaldehyde (DOPAL). The role of the oxidation product of DA in this vicious cycle will be discussed in the following sections. (Created with BioRender.com, accessed on 13 April 2023.)

Figure 2

The pathological implication of dopamine (DA) metabolism. DA is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC), and it is rapidly sequestered into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2), where it is stabilized by the low pH. Following its release into the synaptic cleft, DA reuptake rapidly ensues via the DA transporter (DAT). If the amount of cytosolic DA exceeds the physiological concentration, it can be metabolized via monoamine oxidase (MAO) into 3,4-dihydroxyphenilacetldehyde (DOPAL), a highly toxic molecule that, in turn, is converted to the non-toxic metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) by the enzyme aldehyde dehydrogenase. At cytosolic pH, DA can auto-oxidize leading to the formation of ROS and reactive quinones (DAQs). Both DAQs and DOPAL can react with cytosolic nucleophiles, such as proteins, affecting their functionality and inducing mitochondrial impairment. The interaction between DOPAL and α-synuclein (αSyn) seems to contribute to αSyn-neurotoxicity in Parkinson’s disease. (Created with BioRender.com, accessed on 1 March 2023.)