Research
Introduction
Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. Evidence first emerged following the observation that accidental exposure of drug abusers to 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an inhibitor of complex I of the mitochondrial electron transport chain, resulted in an acute and irreversible parkinsonian syndrome almost indistinguishable from PD. After the discovery that MPTP causes SNpc DA cell death in humans, non-human primates, and in various other mammalian species, this neurotoxin has been used extensively as an experimental animal model of PD. A biochemical link between MPTP toxicity and sporadic PD was subsequently established when several groups reported reduced complex I activity in the SNpc, platelets and skeletal muscle of patients with PD. In addition, cell lines engineered to contain mitochondria derived from platelets of PD patients (cybrids) also exhibit reduced complex I activity. More recently, it was reported that rotenone, another complex I inhibitor, induces a PD-like syndrome in rats. We and others have shown that impairment of mitochondrial respiration by complex I blockade leads to (i) production of free radicals and subsequent oxidative damage to proteins, lipids and DNA, (ii) energy depletion, and (iii) activation of mitochondrial-dependent apoptotic cell death pathways. All of these deleterious events have been shown to play a role in experimental models of PD and have been detected in post-mortem brain samples from PD patients. In addition, the recent identification of PD-causing mutations in the DJ1, PINK1, LRRK2 and Omi/HTRA genes, which are all associated with the mitochondria, further supports a role for mitochondrial dysfunction in PD. However, a primary direct pathogenic role of complex I deficiency in PD-related neurodegeneration remain to be elucidated. In this context, some of our current research projects are aimed at determining the mechanisms and the exact role of mitochondrial dysfunction in PD dopaminergic neurodegeneration.
Additional reading:
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.
Perier C., Tieu K., Guegan C., Caspersen C., Jackson-Lewis V., Carelli V., Martinuzzi A., Hirano M., Przedborski S. and Vila M.
Proceedings of the National Academy of Sciences USA, 102(52):19126-19131 (2005)
Genetic clues to the pathogenesis of Parkinson’s Disease.
Vila M. and Przedborski S.
Nature Medicine, 10 Suppl:S58-62 (2004)
MPTP as a Mitochondrial Neurotoxic Model of Parkinson’s Disease.
Przedborski S., Tieu K., Perier C. and Vila M.
Journal of Bioenergetics and Biomembranes, 36(4):375-9 (2004)
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson’s disease.
Przedborski S. and Vila M.
Annals of the New York Academy of Sciences, 991:189-98 (2003)
The rotenone model of Parkinson’s disease.
Perier C., Bové J., Vila M. and Przedborski S.
Trends in Neuroscience, 26(7):345-6 (2003)
