Although the gene defect responsible for Huntington's disease (HD) has recently been discovered, the means by which it leads to neuronal death remains unknown. We hypothesize that a primary or secondary consequence of the gene defect may be impairment of oxidative phosphorylation. This may then result in both oxidative damage as well as neuronal degeneration by a slow excitotoxic mechanism. We propose to examine this hypothesis using neurochemical studies in both postmortem brain tissue as well as plasma and urine of HD patients. Our first specific aim will be to determine whether there is an abnormality in any of the electron transport chain complexes and ATP synthase in HD postmortem brain tissue as compared with age-matched controls. We will determine whether changes are confined to one enzyme complex and the regional distribution of any changes. If there is defect in oxidative phosphorylation it may lead to increased oxidative damage. Our second specific aim will be to determine if there is evidence of oxidative damage to lipids, proteins or DNA in HD postmortem brain tissue. We will measure 8-hydroxy-2-deoxyguanosine as a marker of oxidative damage to nuclear and mitochondrial DNA, protein carbonyls as a marker of oxidative damage to proteins and malondialdehyde as a marker of oxidative damage to lipids. Our third specific aim is to determine whether there is evidence of impaired oxidative phosphorylation as evidenced by an increase in lactate/pyruvate rations following glucose loading in HD patients. We will also examine whether there is increased formation of 2,3 and 2,5 dihydroxybenzoic acid following salicylate loading, which would be consistent with increased hydroxyl radical generation. Both urine and plasma measurements of 8-hydroxy-2-deoxyguanosine, protein carbonyl groups and other neurochemical markers including hypoxanthine and 3-nitrotyrosine will be determined. If abnormalities are found studies will be undertaken to correlate them with numbers of CAG repeats in both symptomatic and at risk HD patients. Lastly we will determine whether either free radicals or nitric oxide play a role in neuronal degeneration following administration of either malonate or 3-nitropropionic acid. These compounds are succinate dehydrogenase inhibitors which produce lesions which closely resemble HD. If these lesions can be attenuated it would suggest that similar strategies might be useful in HD. These studies will therefore provide direct evidence as to whether there is impairment of oxidative phosphorylaiton and increased oxidative damage in both central and peripheral tissues of HD patients. They also have the potential of leading to novel therapeutic approaches to attempting to slow the degenerative process.

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National Institute of Neurological Disorders and Stroke (NINDS)
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