Journal Article

Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis

Beal, M Flint, Henchcliffe, Claire

2008

Overview

Mitochondrial dysfunction and oxidative stress have been strongly implicated in the pathogenesis of Parkinson disease (PD), and the products of several PD-associated genes become localized to the mitochondria under certain conditions. In this article, Henchcliffe and Beal review recent developments in mitochondrial biology that have contributed to our understanding of the disease process in PD, and they discuss how this knowledge might aid in the development of 'mitochondrial therapies' for PD. 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

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Apoptosis / Autopsies / Biology / Care and treatment / Cell death / Complications and side effects / Cytochrome / Diagnosis / Free radicals / Genetic aspects / Health aspects / Homeostasis / Humans / Medicine / Medicine & Public Health / Metabolism / Mitochondria / Mitochondria - genetics / Mitochondria - pathology / Mitochondrial diseases / Neurology / Oxidative stress / Oxidative Stress - physiology / Parkinson Disease - drug therapy / Parkinson Disease - genetics / Parkinson Disease - physiopathology / Parkinson's disease / Pathogenesis / Phosphorylation / review-article / Risk factors / Ubiquinone - analogs & derivatives / Ubiquinone - therapeutic use / Vitamins - therapeutic use