Oxidative stress in genetic mouse models of Parkinson's disease

Abstract

There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, gene-environment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease.

Figure 1

Pathways leading to oxidative stress in PD and the modulation by PD-related genes. Different pathways contribute to high levels of oxidative stress in dopaminergic neurons, including impaired DA handling (1), mitochondrial dysfunction (2), and neuroinflammation (3). As further discussed in the text, alterations in PD genes can potentiate all these impairments and, therefore, lead to enhanced levels of oxidative stress (see Table 2). UPS dysfunction (4), another important pathogenic pathway in PD, can contribute to the damaging effects of α-syn, due to improper degradation of α-syn mutants or oligomers. Abbreviations: ACO: aconitase, CYT: cytosolic, DA: dopamine, iNOS: inducible nitric oxide synthase, PHOX: NADPH oxidase, UPS: ubiquitin proteasome system, UCP: uncoupling proteins, VESIC: vesicular.

Figure 2

Gene-environment interactions involving oxidative stress in genetic mouse models of PD. Environmental factors and ageing converge to induce cellular oxidative stress, and this can either lead to cell death, or cell survival, based on genetic background. As shown in various gene-environment interaction studies in mouse models of PD (see Table 3), the PD genes can tilt the balance either to cell death, or to cell survival, thereby modulating the survival of the neurons following oxidative damage. Abbreviations: KO: knockout, OExp: overexpression.