Conserved Aging Mechanisms Impacting Dopamine Neuron Survival

项目总结 患帕金森氏症的最大风险因素是年龄，这表明与年龄有关的 大脑的变化容易导致多巴胺(DA)神经元的健康和活性丧失。细胞应激源 如氧化应激和代谢功能障碍等在许多物种中随着年龄的增长而增加，包括 人类和DA神经元特别容易受到氧化应激的影响，因为它们的 代谢需求和内源性活性氧的产生。尽管越来越多的 氧化应激增加与衰老和DA神经元变性有关的证据，氧化的作用 将这种应激与增强的DA神经元脆弱性联系起来的应激反应信号通路 随着年龄的增长，人们对此还没有很好的理解。先前的研究将HIF-1(缺氧诱导因子-1)的激活联系起来 抑制TOR(雷帕霉素靶标)信号的途径和最近的GWAS研究提高了 这些通路的相互作用在调节寿命方面可能很重要，可能在 对细胞应激信号的反应。HIF-1/TOR信号的关键组件也在 人帕金森病黑质DA神经元。这项提议的主要目标是 确定与年龄相关的氧化应激是否导致特定信号的持续上调 HIF-1/TOR信号通路中促进DA神经元对AGE易感性的介体 相关死亡和限制生物寿命。包括果蝇在内的多种动物模型的研究 提示TOR去调控是神经系统老化和神经退行性疾病的一个特征。 我们将利用果蝇遗传背景集合中的自然遗传变异 我们发现影响活性氧产生、寿命和DA神经元活性的因素 两个主要目标：首先，我们将研究衰老对大脑氧化应激表达的影响 在整个大脑中以及在特定的脆弱(即DA)和备用的信号媒介 神经元群。第二，我们将确定这些信号中介在与年龄相关的 DA神经元死亡和寿命。这些探索性研究将为详细的 衰老和与年龄相关的压力如何驱动该信号的上游调节因子的特征 途径，并为有关这些信号介质在帕金森病中的作用的更广泛的研究提供信息 神经退化与额外的遗传和环境因素有关。

PROJECT SUMMARY The single biggest risk factor for developing Parkinson’s disease is age, suggesting that age-related changes in the brain predispose to loss of dopamine (DA) neuron health and viability. Cell stressors such as oxidative stress and metabolic dysfunction increase with age in many species including humans, and DA neurons are particularly vulnerable to oxidative stress because of their high metabolic demands and intrinsic reactive oxygen species production. Despite a growing body of evidence linking elevated oxidative stress to aging and DA neuron degeneration, the role of oxidative stress-responsive signaling pathways in connecting this stress to enhanced DA neuron vulnerability with age are not well understood. Prior studies link activation of the HIF-1 (hypoxia-inducible factor-1) pathway to suppression of TOR (target of rapamycin) signaling and recent GWAS studies raise the possibility that the interaction of these pathways may be important in regulating lifespan, possibly in response to cellular stress signals. Key components of HIF-1/TOR signaling are also altered in human Parkinson’s disease substantia nigra DA neurons. The primary goal of this proposal is to determine whether age-related oxidative stress results in sustained upregulation of specific signaling mediators in the HIF-1/TOR signaling pathway that promote susceptibility of DA neurons to age- related death and limit organismal lifespan. Studies from multiple animal models including Drosophila indicate that TOR deregulation is a feature of nervous system aging and neurodegenerative disease. We will leverage the natural genetic variation in a collection of Drosophila genetic backgrounds that we find influences reactive oxygen species production, lifespan and DA neuron viability to achieve two primary goals: First, we will examine the effects of aging on brain expression of oxidative stress signaling mediators both in the whole brain as well as in specific vulnerable (i.e. DA) and spared neuronal populations. Second, we will determine the role of these signaling mediators on age-related DA neuron death and lifespan. These exploratory studies will pave the way for detailed characterization of how aging and age-related stress drives upstream regulators of this signaling pathway, and inform broader studies on the role of these signaling mediators in Parkinson’s disease neurodegeneration linked to additional genetic and environmental factors.