Dopamine-Mediated Oxidative Stress Associated with Neurodegeneration in Parkinson Disease

Dopamine-mediated neurotoxicity has been speculated as a potential contribution to the pathogenesis of Parkinson disease (PD), including a diffuse protein aggregation pathology but relatively selective death of dopaminergic neurons in the substantia nigra. The dopamine-mediated oxidative stress, produced by dopamine oxidation resulting in reactive oxygen species (ROS) and reactive dopamine quinones, is hypothesized to be the key event in the specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and neurotoxininduced parkinsonism. The cytotoxity in dopaminergic neurons occurs primarily due to the generation of highly reactive cyclized O-quinones, which damage mitochondia by opening the mitochondrial permeability transition pore, leading to cell death. These toxic quinones conjugate with several key PD pathogenic molecules, such as tyrosine hydroxylase, a-synuclein and parkin, forming a complex of protein-bound-quinone (quinoprotein), consequently inhibiting enzyme/protein function. Furthermore, cyclized dopamine quinones also inhibit proteasome activity, resulting in protein aggregation that may facilitate Lewy body formation in PD. Dopamine quinone formation is also closely linked to other representative hypotheses for PD. However, reductants such as glutathione (GSH), ascorbic acid (AA), and superoxide dismutase (SOD) may protect dopaminergic neurons from dopamineinduced toxicity or by various other biochemical insults associated with PD. The chaperone heat-shock protein 70 (HSP70) reduces protein misfolding and aggregation in cells, implicating its protective role against a variety of insults including oxidative stress. There are several pathogenic mechanisms possibly involved with death of dopaminergic neurons, but this overview focuses on dopamine-mediated oxidative stress that may contribute to selective neurodegeneration of dopaminergic neurons in PD.

Keywords: Parkinson disease; dopamine; dopaminergic neurons, dopamine quinones; quinoprotein; oxidative stress; neuroinflammation; glutathione conjugation