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Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis

Nature Clinical Practice Neurology volume 4, pages 600–609 (2008)Cite this article

Abstract

Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.

Key Points

  • Defective mitochondrial function and increased oxidative stress have been demonstrated in a subset of people with Parkinson disease (PD)

  • The products of several nuclear genes associated with PD are linked to mitochondrial function

  • Mitochondrial activity can also be affected by environmental factors that possibly contribute to PD pathogenesis

  • Novel therapies that target mitochondrial function and oxidative stress, such as coenzyme Q10, are now in clinical trials to test whether they modify PD progression

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Figure 1: Mitochondrial dysfunction affects diverse cellular processes that can culminate in cell death.
Figure 2: Products of PD-associated genes that affect mitochondrial function and oxidative stress.

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Acknowledgements

The authors would like to thank Ms Greta Strong for her outstanding assistance, and Penelope Grossman M.D. for helpful comments on the manuscript. CH acknowledges support of the Daisy and Paul Soros Clinical Scholarship in Neurology.

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  1. C Henchcliffe is the Daisy and Paul Soros Clinical Scholar in Neurology and MF Beal is the Anne Parrish Titzell Professor and Chairman of the Department of Neurology and Neuroscience at the Weill Medical College of Cornell University, New York, NY, USA.,

    Claire Henchcliffe & M Flint Beal

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Correspondence to Claire Henchcliffe.

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Henchcliffe, C., Beal, M. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Rev Neurol 4, 600–609 (2008). https://doi.org/10.1038/ncpneuro0924

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