Autism is a neurodevelopmental disorder likely caused by a complex interaction of multiple genes and environmental factors. Recent advances indicate the involvement of oxidative stress in the pathology of autism. We have described a plasma metabolic profile indicative of compromised glutathione-mediated redox capacity and oxidative stress in children with autism. Glutathione (GSH), the major intracellular antioxidant is synthesized in all cells; thus, our plasma findings likely reflect systemic glutathione redox imbalance. We hypothesized that glutathione redox imbalance is systemic and contributes to the functional alterations associated with autism including immune and mitochondrial dysfunction. The first aim of this project was to measure the glutathione redox state and biomarkers of oxidative stress and inflammation in peripheral blood mononuclear cells (PBMC) and post-mortem brain from individuals with autism and unaffected controls. We demonstrated glutathione redox imbalance in PBMC from children with autism that was accompanied by increased monocyte proinflammatory cytokine production. In addition, glutathione redox imbalance in cerebellum and BA22 samples from individuals with autism was associated with elevated markers of oxidative protein/DNA damage, inflammation and mitochondrial superoxide production. The second aim of this project was to investigate the mitochondrial function of autism and control lymphoblastoid cell lines (LCLs) before and after a pro-oxidant exposure and to determine whether increasing the intracellular glutathione redox capacity of the autism LCLs reduces susceptibility to mitochondrial dysfunction. We found increased mitochondrial reserve capacity in autism LCLs at baseline; however, following a pro-oxidant exposure, autism LCLs exhibited a greater depletion of reserve capacity relative to controls. Increasing the intracellular glutathione levels in autism LCLs reduced the susceptibility to oxidant-induced mitochondrial dysfunction. These studies demonstrate that glutathione redox imbalance in autism is systemic and associated with increased monocyte proinflammatory cytokine production and with oxidative damage, inflammation and mitochondrial superoxide production in the brain. Furthermore, oxidant-induced mitochondrial dysfunction in autism LCLs is mediated by reduced intracellular glutathione-mediate redox capacity. These data suggest that a reduced ability to resolve oxidative stress due to decreased glutathione-mediated redox capacity contributes to immune and mitochondrial dysfunction in autism. Targeting treatments to correct glutathione redox imbalance may improve the symptoms associated with autism.
|Advisor:||James, S. Jill|
|Commitee:||Barger, Steve W., Drew, Paul D., Gilbert, Kathleen, MacMillan-Crow, Lee Ann|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology, Immunology|
|Keywords:||Autism, Glutathione redox imbalance, Inflammation, Mitochondrial dysfunction|
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