DOPAMINERGIC NEUROTOXINS AND AGING

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DESCRIPTION: (Applicant's abstract) Parkinson's Disease (PD), a neurodegenerative disorder of unknown etiology which afflicts a large number of our elderly, is characterized by a massive loss of midbrain dopaminergic (DA) neurons and some loss of noradrenergic (NA) and serotonergic (5HT) neurons in the locus coreuleus and raphe nuclei, respectively. The goal of the proposed research is to investigate the potential neuroprotective role of synaptic vesicles in monoaminergic neurons. The hypothesis is that synaptic vesicles within various populations of monoaminergic neurons can provide a storage compartment for neurotoxins and thus reduce the amount of free toxin in the cytosol capable of producing damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite 1-methyl-4-phenylpryidinium (MPP+) will be used because they are potent neurotoxins and because MPP+ is an excellent substrate for the synaptic vesicle monoamine transporter. There are marked differences in the susceptibility of rats and mice to MPTP-induced degeneration of DA neurons which is not associated with the amount of MPP+ to which the neurons are exposed. These findings suggest that there may be a much greater intracellular sequestration of MPP+ within DA neurons in rats as compared to mice. This species difference in neurotoxic response will be used to test the hypothesis. In other studies, the role of vesicular sequestration in NA and 5HT neurons and MPTP toxicity will be evaluated. A multidisciplinary approach will be utilized, including in vivo and in vitro studies, neurochemical and immunohistochemical studies. The specific aims of this project are: 1) to determine if differences in the capacity of vesicles obtained from the neostriata of rats or mice to accumulate MPP+ contribute to the species differences in the sensitivity of dopaminergic neurons to MPTP/MPP+-induced neurotoxicity; 2) to further examine in vivo the degeneration of monoaminergic neurons produced by the administration of MPTP to mice with dysfunctional vesicles; 3) to examine if reserpinization of animals affects MPTP biodistribution of MPP+ accumulation within the brain; 4) to compare dose-response curves for damage produced by intrastriatal infusions of MPP+ in mice and rats treated with or without a vesicular uptake inhibitor. The possibility that vesicles might provide a storage site for exogenous or endogenous neurotoxins is a novel and intriguing concept. This in turn raises the question as to whether defects in vesicular function of monoaminergic neurons might contribute to the neurodegeneration seen in PD.