Oxidative stress and mitochondria: Implications for Parkinson's disease.
Item
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Title
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Oxidative stress and mitochondria: Implications for Parkinson's disease.
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Identifier
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AAI9618116
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identifier
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9618116
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Creator
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Werner, Peter.
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Contributor
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Adviser: Gerald Cohen
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Date
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1996
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry | Biology, Neuroscience | Health Sciences, Pharmacology | Biology, Cell | Biology, Animal Physiology
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Abstract
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Oxidative stress as a mechanism of disease has been implicated in a wide variety of chronic and acute degenerative disorders, including disorders of the central nervous system (CNS), ischemic heart damage and rheumatic diseases. In recent years, oxidative stress has also become a prominent working hypothesis in a number of neurodegenerative disorders, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The work described here focused on the hypothesis that the chemical and biochemical characteristics of dopamine (DA) and its physiological precursor, L-dopa, may lead or contribute to an oxidative stress in Parkinson's disease. Prior evidence for this possibility was found in this and other laboratories. The interest in these two molecules stems from the fact that the neurons mostly affected in PD use DA as their neurotransmitter, and that the major therapy for PD is DA replacement therapy via L-dopa. The research presented here was to investigate the effect of DA and L-dopa on cellular respiration and its organelle, the mitochondrion. The experimental systems used were isolated mitochondria from rat brain or liver or mouse liver (studies with DA) and cultured human embryonic fibroblasts (L-dopa and DA). DA is catabolized by monoamine oxidase (MAO), generating {dollar}\rm H\sb2O\sb2{dollar} in the process. Experiments in isolated mitochondria showed that MAO catalyzed turnover of DA increases the levels of glutathione disulfide (GSSG) and protein mixed-disulfides (PrSSG) in mitochondria. This demonstrates that DA turnover by MAO can affect the thiol-redox state in mitochondria. Furthermore, the increases in GSSG and PrSSG were accompanied by a reduction in the activity of aldehyde dehydrogenase, an enzyme localized to the mitochondrial matrix. In the experiments with human fibroblasts, exposure of cells to L-dopa partially inhibited cellular respiration, which was attributed to reactive species generated during autoxidation of the catechol function of L-dopa. L-dopa is commonly used in the treatment of Parkinson's disease, as DA replacement therapy. Both DA and L-dopa had negative effects on mitochondrial function in the experiments conducted for this thesis. Since a major form of treatment for Parkinson's disease is L-dopa supplementation, these findings raise again the issue of preventing or ameliorating oxidative stress as a therapeutic approach in the treatment of Parkinson's disease.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
