Conserved Aging Mechanisms Impacting Dopamine Neuron Survival

项目摘要 帕金森病的最大风险因素是年龄，这表明与年龄有关的 大脑中的变化易使多巴胺（DA）神经元健康和活力丧失。细胞应激原 例如氧化应激和代谢功能障碍在许多物种中随着年龄增长而增加 人类，DA神经元特别容易受到氧化应激的影响，因为它们的高 代谢需求和内在活性氧产生。尽管越来越多的 将氧化应激升高与衰老和DA神经元变性联系起来的证据， 应激反应信号通路将这种应激与增强的DA神经元脆弱性联系起来 随着年龄的增长，人们并不了解。先前的研究与HIF-1（缺氧诱导因子-1）的激活有关 抑制TOR（雷帕霉素靶点）信号传导的途径和最近的GWAS研究提出了 这些途径的相互作用可能在调节寿命方面很重要， 对细胞应激信号的反应。HIF-1/TOR信号传导的关键成分也在细胞内发生改变。 人帕金森病黑质DA能神经元。该提案的主要目标是 确定年龄相关的氧化应激是否导致特异性信号传导的持续上调 HIF-1/TOR信号通路中的介质，促进DA神经元对年龄的敏感性， 相关的死亡和有限的有机体寿命。包括果蝇在内的多种动物模型的研究 表明TOR失调是神经系统老化和神经变性疾病特征。 我们将利用果蝇遗传背景中的自然遗传变异， 我们发现影响活性氧的产生，寿命和DA神经元的活力，以实现 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。 信号介质在整个大脑以及在特定的脆弱（即DA）和幸免 神经元群体。第二，我们将确定这些信号介质对年龄相关的 DA神经元死亡和寿命。这些探索性研究将为详细的 表征衰老和年龄相关的压力如何驱动这种信号传导的上游调节因子 通路，并为更广泛的研究提供信息，这些信号介质在帕金森病中的作用 神经退行性变与其他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.