Complex I Inhibition in Cultured Cells as Model for Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra (SN) pars compacta. The etiology of PD is largely unknown. The finding that l-methyl-4-phenyl-l,2,3,6 tetrahydropyridine (MPTP) induces parkinsonism in humans, primates and rodents and inhibits NADH: ubiquinone oxidoreductase (complex I) of the respiratory chain has directed PD research towards this enzyme (Nicklas et al., 1985). Among the biochemical abnormalities observed in the brains of PD patients is a defect in complex I (Schapira et al., 1990). In the brain, this deficiency is specific for the SN. It is, however, also found peripherally in platelets, fibroblasts and muscle of PD patients (Swerdlow et al., 1996). The resulting decrease in mitochondrial energy (ATP) production of SN neurons might directly induce programmed cell death (PCD, apoptosis) and/or contribute to an increased vulnerability of these neurons by neurotoxins or endogenous glutamate. Both mechanisms may thus contribute to the progression of PD. Restoration of the energy balance in complex I deficient dopaminergic neurons may therefore prevent the progression of PD.