COMPLEX-I DEFICIENCY WHAT THE MPTP MODEL TEACHES US

A major feature in the etiology of Leber's hereditary optic neuropathy (LHON) is inhibition of mitochondrial complex I activity. However, li ttle is known about why this genetic lesion is so tissue-specific. Stu dies in this laboratory on the cellular mechanisms of neurodegeneratio n have focused on the propensity of some endogenous and environmental chemicals to cause neurotoxicity that appears to be associated with di sturbances in neuronal energy metabolism and may be mediated by glutam ate receptors. Recognition of these processes has not only allowed ela boration of the mechanism of action of these chemicals and suggested a role for them in human disease, but also has furnished useful animal models of human neurodegenerative disorders. This report deals with th e use of 1-methyl-4-phenyl-1-1,2 3, 6,-tetrahydropyridine (MPTP) and i ts analogs to produce an important animal model of Parkinson's disease . The mechanism whereby these substances cause cell death may provide insights into the pathophysiology of Parkinson's disease. The metaboli te of MPTP, 1-methyl-4-phenylpyridine, is the true toxin; it apparentl y acts by blocking mitochondrial complex I activity in the basal gangl ia after selective uptake into the dopaminergic neurons. This model ma y be important not only as a paradigm for drug testing, but may also h elp define the etiology of other disorders, including LHON, that invol ve mitochondrial dysfunction.