Role of GSH and MAO-B in PD-related mito dysfunction

GSH 和 MAO-B 在 PD 相关线粒体功能障碍中的作用

• 批准号: 6871734
• 负责人: Julie Kay Andersen
• 金额: $ 44.86万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871734
• 关键词: Krebs' cycle; Parkinson' s disease; age difference; aging; amine oxidase (flavin); cell line; chronic disease /disorder; dopamine; enzyme activity; enzyme complex; gene expression; genetically modified animals; glia; glutathione; laboratory mouse; methylphenyltetrahydropyridine; mitochondrial disease /disorder; neural degeneration; nicotinamide adenine dinucleotide; oxidative stress; protein metabolism; psychomotor function; substantia nigra; tissue /cell culture; transfection; Krebs' cycle; Parkinson' s disease; age difference; aging; amine oxidase (flavin); cell line; chronic disease /disorder; dopamine; enzyme activity; enzyme complex; gene expression; genetically modified animals; glia; glutathione; laboratory mouse; methylphenyltetrahydropyridine; mitochondrial disease /disorder; neural degeneration; nicotinamide adenine dinucleotide; oxidative stress; protein metabolism; psychomotor function; substantia nigra; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Increased activity of the hydrogen peroxide-producing enzyme monoamine oxidase B (MAO-B) and decreased levels of the peroxide-scavenging compound glutathione (GSH) have both been postulated to contribute to the selective demise of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD) via production of chronic oxidative stress in these cells. Oxidative stress may in turn impinge on mitochondrial function contributing to their subsequent neurodegeneration. Loss of mitochondria function in PD has been proposed to be the result of selective inhibition of mitochondrial complex I activity, however the specific cause or causes leading to its repression are unknown. We have recently demonstrated that subtle elevations in MAO-B or decreases in GSH in dopaminergic PC12 cells in vitro akin to that which occurs during brain aging or PD result in decreased mitochondriaI complex I activity. This appears to involve both direct oxidative damage to the complex itself as well as inhibition of the TCA enzyme alpha-ketoglutarate dehydrogenase (KDGH) which provides NADH as substrate to the complex. This in turn affects the capacity of the organelle to maintain function under stress conditions. As a logical extension of our published in vitro studies, we propose to analyze mitochondrial function and neurodegeneration in transgenic mouse lines created in our laboratory which possess inducibly increased levels of glial MAO-B mimicking those which occur during aging or decreases in GSH such as occurs in PD. This will allow us to assess the effects of this phenomenon on dopaminergic neurons of the SN which undergo degeneration in PD in the context of aging and stress. The ability to induce these changes in our transgenic models will allow us to examine the consequences of elevation in the adult animal bypassing any confounding developmental effects in a dosage-dependent and reversible manner. By looking throughout the lifespan, we will be able to assess the role that aging itself plays in this process. Information gleaned through these studies will allow us to test in future therapeutic strategies to minimize the effects of these alterations on mitochondrial function as it relates to PD and associated neurodegeneration.

DESCRIPTION (provided by applicant): Increased activity of the hydrogen peroxide-producing enzyme monoamine oxidase B (MAO-B) and decreased levels of the peroxide-scavenging compound glutathione (GSH) have both been postulated to contribute to the selective demise of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD) via production of chronic oxidative stress in这些细胞。氧化应激反过来可能会影响线粒体功能，从而导致其随后的神经变性。已经提出，PD中线粒体功能的丧失是选择性抑制线粒体复合物I活性的结果，但是导致其抑制的特定原因或原因尚不清楚。我们最近证明，多巴胺能PC12细胞的MAO-B或GSH的微妙升高与在脑衰老或PD期间发生的升高相似，导致线粒体复合物I活性降低。这似乎涉及对复合物本身的直接氧化损伤，也涉及抑制TCA酶α-酮戊二酸脱氢酶（KDGH），该脱氢酶（KDGH）为NADH提供了作为复合物的底物。反过来，这会影响细胞器在应力条件下保持功能的能力。作为我们已发表的体外研究的逻辑扩展，我们建议分析我们实验室中创建的转基因小鼠系中的线粒体功能和神经退行性，该系在我们的实验室中产生的，具有诱人的神经胶质MAO-B水平，模仿衰老过程中发生或减少GSH的GSH中发生的胶质MAO-B水平。这将使我们能够评估这种现象对SN的多巴胺能神经元的影响，该神经元在衰老和压力的背景下在PD中发生变性。在我们的转基因模型中诱导这些变化的能力将使我们能够检查成年动物中升高的后果，以剂量依赖性和可逆的方式绕过任何混杂的发育效果。通过在整个生命周期中查看，我们将能够评估老化本身在此过程中所扮演的角色。通过这些研究收集的信息将使我们能够测试将来的治疗策略，以最大程度地降低这些改变对线粒体功能的影响，因为它与PD和相关的神经变性有关。