Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis.
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.
Henchcliffe
Claire
C
Department of Neurology and Neuroscience at the Weill Medical College of Cornell University, New York, NY 10021, USA. clh2007@med.cornell.edu
Beal
M Flint
MF
D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use
D014815:Vitamins; D014451:Ubiquinone; C024989:coenzyme Q10