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

描述（由申请人提供）：多巴胺能神经元变性导致帕金森病，在老年人中非常普遍。帕金森病是第二常见的神经退行性疾病和最常见的运动障碍，其特征在于控制运动、情绪和动机的腹侧中脑黑质多巴胺能神经元的丧失。大多数帕金森病病例是年龄依赖性和散发性的，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，已被证明有助于散发性帕金森病中多巴胺能神经元的变性。但氧化应激诱导多巴胺能神经元变性的分子机制仍不清楚。 该提案旨在使用MPTP处理的小鼠作为氧化应激诱导的帕金森病模型，与基因敲除小鼠和培养的多巴胺能神经元一起阐明氧化应激如何诱导多巴胺能神经元变性。具体来说，这项建议将集中在SIRT 1，NAD依赖性蛋白脱乙酰酶，这是一个主调节应激反应，和叉头转录因子FOXA 2，这是最近被证明是专门表达在小鼠腹侧中脑多巴胺能神经元调节其生存和发展。该提案计划描述SIRT 1对多巴胺能神经元氧化应激反应中FOXA 2的脱乙酰化，并解决包括SIRT 1在体内使FOXA 2脱乙酰化的位点、这些脱乙酰化事件如何影响FOXA 2活性以及SIRT 1是否参与调节多巴胺能神经元对体内氧化应激反应的变性等问题。 总之，这些研究将测试SIRT 1和SIRT 1介导的FOXA 2脱乙酰化在帕金森病发病机制中的新作用。拟议研究的结果还将为氧化应激诱导的多巴胺能神经元变性的分子机制提供新的见解，这有望带来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。

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.