There is now increasing evidence that neuronal damage in the-age-related neurodegenerative diseases is mediated by the mechanism of oxidative stress. Oxidative stress occurs when there is an overproduction of reactive oxygen species (ROS), an underactivity of cellular defense mechanisms, or both, leading to uncontrolled oxidation of critical biological molecules. The products of such oxidative attack on macromolecules include the formation of lipid hydroperoxides and aldehyde breakdown products, nitrotyrosine and carbonyl modifications of proteins, and DNA hydroxylation. Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam displays many similarities to the age-related neurodegenerative diseases but with an earlier onset and much higher prevalence suggesting that ALS/PDC recapitulates the pathogenetic mechanism(s) of the age-related neurodegenerative diseases at an intense level. We have developed evidence of oxidative damage in ALS/PDC and the neurodegenerative diseases of aging, suggesting that the mechanism of oxidative stress participates in producing neuronal degeneration. In both ALS/PDC and Alzheimer's disease we have shown evidence of nitrated tyrosine residues localized to neurofibrillary tangles of the hippocampus and entorhinal cortex, and in both ALS/PDC and idiopathic Parkinson's disease we have demonstrated increased iron concentrations within dopaminergic neurons of the substantia nigra. In this project, we will further examine cases of ALS/PDC for evidence of oxidative damage. The end products of oxidative damage to cellular structures that we will investigate include lipid peroxidation (malondialdehyde), protein nitration (nitrotyrosine), protein oxidation (protein carbonyls) and DNA hydroxylation (8-OlI-dG). We will also investigate the potential for oxidative stress to develop as a result of increased intraneuronal iron, decreased ferritin or a decrease in glutathione content. Low molecular weight iron, unprotected by storage in ferritin, can mediate the oxidation of macromolecules initiating lipid peroxidation, DNA hydroxylation or site specific protein oxidation. Protection against an increase in available iron, and therefore the production of ROS, is accomplished by increasing iron storage capacity in response to increases in intracellular free iron. Glutathione, the major defense against ROS produced in the brain, is oxidised by glutathione peroxidase reducing hydrogen peroxide to water. A decline of cellular glutathione content, implicated in Parkinson's disease, will cause a decrease in the removal of hydrogen peroxide and an increase in the potential for the generation of hydroxyl radicals.
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