Aging Stress Pathway and Dopaminergic Neuron Degeneration in Parkinson's Disease

帕金森病的衰老应激途径和多巴胺能神经元变性

• 批准号: 8726273
• 负责人: Yongchao Charles Ma
• 金额: $ 18.38万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726273
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 4-phenyl-1,2,3,6-tetrahydropyridine; Acetylation; Address; Affect; Age; Aging; Antibodies; Behavior; Biological Assay; Cells; Deacetylase; Deacetylation; Defect; Development; Diagnosis; Disease; Disease model; Elderly; Energy Metabolism; Event; Exposure to; Herbicides; Human; In Vitro; Knockout Mice; Lead; Link; Liver; Luciferases; Mediating; Midbrain structure; Molecular; Monitor; Moods; Motivation; Motor; Movement; Movement Disorders; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Stress; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Process; Proteins; Reporter; Research; Role; Site; Stress; Substantia nigra structure; Symptoms; System; Testing; Tissues; Toxic Environmental Substances; Western Blotting; age related; biological adaptation to stress; dopaminergic neuron; forkhead protein; glucose metabolism; in vivo; inhibitor/antagonist; insight; lipid metabolism; mouse model; nestin protein; novel; public health relevance; response

DESCRIPTION (provided by applicant): Dopaminergic neuron degeneration leads to Parkinson's disease, which is highly prevalent in older adults. As the second most common neurodegenerative disease and the most common movement disorder, Parkinson's disease is characterized by the loss of ventral midbrain substantia nigra dopaminergic neurons that control movement, mood, and motivation. Most cases of Parkinson's disease are age-dependent and sporadic, with about 5% are familial. Oxidative stress, including that induced by environmental toxicant 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and herbicide Paraquat, has been demonstrated to contribute to dopaminergic neuron degeneration in sporadic Parkinson's disease. But the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration remains largely unknown. This proposal aims to use MPTP-treated mice as an oxidative stress-induced Parkinson's disease model, together with knockout mice and cultured dopaminergic neurons to elucidate how oxidative stress can induce dopaminergic neuron degeneration. Specifically, this proposal will focus on SIRT1, a NAD-dependent protein deacetylase that is a master regulator of stress response, and forkhead transcription factor FOXA2, which was recently shown to be specifically expressed in mouse ventral midbrain dopaminergic neurons regulating their survival and development. This proposal plans to characterize the deacetylation of FOXA2 by SIRT1 in response to oxidative stress in dopaminergic neurons, and to address questions including what sites does SIRT1 deacetylate FOXA2 in vivo, how do these deacetylation events affect FOXA2 activity, and whether SIRT1 is involved in regulating dopaminergic neuron degeneration in response to oxidative stress in vivo. Together, these studies will test the novel roles of SIRT1 and SIRT1-mediated deacetylation of FOXA2 in Parkinson's disease pathogenesis. Findings from the proposed research will also provide new insights into the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration, which will hopefully lead to new strategies to better diagnose and treat Parkinson's disease and other neurodegenerative disorders.

描述(申请人提供)：多巴胺能神经元变性导致帕金森氏症，这是非常普遍的老年人。作为第二常见的神经退行性疾病和最常见的运动障碍，帕金森病的特点是腹侧中脑黑质多巴胺能神经元的丢失，这些神经元控制着运动、情绪和动机。帕金森氏症患者大多呈年龄依赖性和散发性，约5%是家族性的。氧化应激，包括环境毒物1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)和除草剂百草枯诱导的氧化应激，已被证明与散发性帕金森病的多巴胺能神经元变性有关。但氧化应激诱导的多巴胺能神经元变性的分子机制在很大程度上仍不清楚。这项建议旨在用MPTP处理的小鼠作为氧化应激诱导的帕金森病模型，以及基因敲除小鼠和培养的多巴胺能神经元，以阐明氧化应激如何诱导多巴胺能神经元变性。具体地说，这项建议将集中在SIRT1，一种依赖NAD的蛋白去乙酰酶，它是应激反应的主要调节因子，以及叉头转录因子FOXA2，最近被证明在小鼠腹侧中脑多巴胺能神经元中特异表达，调节它们的生存和发育。本研究计划研究氧化应激下SIRT1对FOXA2的脱乙酰化作用，并探讨SIRT1脱乙酰化FOXA2在体内的作用部位，这些脱乙酰化事件如何影响FOXA2的活性，以及SIRT1是否参与体内氧化应激引起的多巴胺能神经元变性的调节。总之，这些研究将测试SIRT1和SIRT1介导的FOXA2脱乙酰化在帕金森病发病机制中的新作用。这项拟议的研究结果还将为氧化应激诱导多巴胺能神经元变性的分子机制提供新的见解，这将有望导致更好地诊断和治疗帕金森病和其他神经退行性疾病的新策略。