Biochemical studies have revealed defects in enzymes of oxidative phosphorylation in tissue samples from patients with neurodegenerative diseases. Respiratory chain deficiencies induced by exogenous or endogenous toxins serve as important models in elucidating the etiology and pathogenesis of these disorders. The administration of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) to animals produces damage to nigrostriatal dopamine (DA) neurons. The MPTP model of PD involves the conversion of MPTP to MPP+, which then inhibits complex I of the electron transport chain. Moreover, the complex II inhibitor, malonate,causes cell loss in multiple neuronal populations, including dopamine and GABA. The neurons of the basal ganglia and substantia nigra appear to be particularly susceptible to impairments in energy metabolism. The presence of DA in these regions may contribute to the effects of a metabolic stress because the neurotransmitter can inhibit NADH dehydrogenase and also autooxidize to form cytotoxic quinones. An excitotoxic component has been implicated in both MPTP and malonate-induced toxicities, but the contribution of excitotoxicity has remained controversial. If it can be shown that there is a link between metabolic inhibition and either direct or indirect actions of DA, this study will have important applications towards the development and/or utilization of therapeutic agents in neurodegenerative disorders of the basal ganglia.
