Oxidative stress and Parkinson's disease

Abstract

Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.

Keywords: Parkinson disease; dopamine; mitochondrial dysfunction; neuroinflammation; oxidative stress.

FIGURE 1

Suggested physiological processes related to pathogenesis of Parkinson’s disease (PD). Different pathways and their dysfunctions resulting from genetic modifications in PD-related genes and lead to an increased oxidative stress. Mutations or altered expression of these proteins result in mitochondrial impairment, oxidative stress, and protein misfolding. Also, dopamine metabolism may be oxidized to reactive dopamine quinones contributing to increased levels of reactive oxygen species. α-Synuclein becomes modified and accelerate its aggregation. Increased oxidative stress provokes impaired function of the UPS that degrades misfolded or damaged proteins and hereby further affecting cell survival. Environmental toxins impair mitochondrial function, increase the generation of free radicals, and lead to aggregation of proteins, including α-synuclein. Mitochondrial dysfunction by complex I inhibition affects by adding an increase in oxidative stress and a decline in ATP production, leading to damage of intracellular components and to cell death. Also, neuroinflammatory mechanisms might contribute to the cascade of consequences leading to cell death. In summary, all these several cellular mechanisms attributed to oxidative stress are implicated in the selective degeneration of dopaminergic neurons.