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

描述（由申请人提供）：多巴胺能神经元退化导致帕金森病，这在老年人中非常普遍。作为第二常见的神经退行性疾病和最常见的运动障碍，帕金森病的特点是失去控制运动、情绪和动机的腹侧中脑黑质多巴胺能神经元。大多数帕金森氏症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的多巴胺能神经元变性。但是氧化应激诱导的多巴胺能神经元变性的分子机制仍然是未知的。本课题旨在利用mptp处理小鼠作为氧化应激诱导的帕金森病模型，与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，本研究将重点关注SIRT1和叉头转录因子FOXA2，前者是一种nad依赖性蛋白去乙酰化酶，是应激反应的主要调节因子，后者最近被证明在小鼠腹侧中脑多巴胺能神经元中特异性表达，调节其生存和发育。本研究计划对多巴胺能神经元氧化应激时SIRT1对FOXA2的去乙酰化进行表征，并解决包括SIRT1在体内哪些位点对FOXA2进行去乙酰化，这些去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时多巴胺能神经元变性的调节等问题。总之，这些研究将测试SIRT1和SIRT1介导的FOXA2去乙酰化在帕金森病发病机制中的新作用。该研究的发现也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，这将有望为更好地诊断和治疗帕金森病和其他神经退行性疾病提供新的策略。

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.