Dopamine Toxicity in Models of Huntington's Disease

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DESCRIPTION (Adapted from applicant's abstract): The overall goal of this application is to elucidate the roles of dopamine and the enzyme monoamine oxidase in models of Huntington's disease [HD]. Huntington's disease is a progressive neurodegenerative disorder, the pathogenesis of which is [not] completely understood. In patients with Huntington's disease, there is a mutation in the gene encoding the protein huntingtin, which results in an expanded polyglutamine sequence leading to degeneration of the basal ganglia. There is mounting evidence that metabolism of the transmitter dopamine by the enzyme monoamine oxidase, in cells in which an underlying metabolic defect exists, may lead to a cascade of events resulting in neuronal dysfunction and death. Specific Aim 1. Will determine the degree to which dopamine enhances, and MAO inhibitors attenuate, parameters of oxidative stress, mitochondrial function and neuron death in neuronal culture and mice treated with the mitochondrial inhibitor 3-nitropropionic acid. The advantage of 3-nitropropionic acid is that it provides a model of Huntington's disease resulting from relatively "pure" defect in energy production. Specific Aim 2, will examine the effects of dopamine and MAO inhibitors on these same parameters in PC6 cells transfected with full- length mutant huntingtin and cells transfected with differing lengths of polyglutamine expansions. The use of these different constructs will allow the "dose-response" relationship between polyglutamine length and toxicity to be determined and the specificity of mutant huntingtin-conferred susceptibility to DA to be established. Lastly, Specific Aim 3 will determine whether dopamine enhances, and MAO inhibitors attenuate/delay, the biochemical and neuropathological as well as behavioral abnormalities and survive in transgenic mice transfected with the first exon of the huntingtin gene. The results of these studies will demonstrate the critical role that metabolism of dopamine plays in striatal neuron death in Huntington's disease and offer a potentially novel therapeutic approach for the treatment of this disorder.