Exploring the Neuroprotective Potential of Tobacco and Coffee in Fly Models of PD

描述(申请人提供)：帕金森病(PD)是一种常见的高度衰弱的运动障碍，由中脑多巴胺能神经元退化引起。帕金森病发病的分子机制尚不清楚，目前尚无预防性治疗方法。旨在确定影响帕金森病发病率的环境因素的流行病学研究提供了压倒性的数据，支持咖啡和烟草使用者患帕金森病的风险大大降低。虽然对这些发现有几种可能的解释，但我们假设烟草和咖啡含有赋予神经保护作用的化学物质。为了验证这一假设，我们使用了两种不同的果蝇帕金森病模型。具体地说，我们在工作中使用的两个PD模型包括一个携带parkin基因零等位基因的果蝇品系，以及一个过度表达人类1-突触核蛋白的转基因果蝇品系。我们的两种果蝇模型都表现出帕金森病的多种特征，最显著的是，中枢神经系统中的多巴胺能神经元选择性变性。在初步研究中，我们使用我们的苍蝇PD模型来测试烟草和咖啡提取物的神经保护潜力，并将这些提取物与尼古丁和咖啡因的神经保护作用进行比较，尼古丁和咖啡因分别是烟草和咖啡的可疑神经保护剂。我们的研究表明，在我们的两种果蝇模型中，咖啡和烟草确实具有神经保护作用。然而，尼古丁和咖啡因本身似乎并不能提供神经保护，这表明烟草和咖啡中的神经保护成分是新的化学物种。目前的应用有两个主要目标：第一个目标涉及烟草和咖啡的神经保护成分的鉴定和结构特征；第二个目标涉及实验，以确定烟草和咖啡提供神经保护的机制。果蝇是这些研究的理想选择，因为这种生物的短代时间、强大的遗传工具以及神经退行性疾病机制的进化保守性将使我们能够以一种与人类相关的方式快速有效地探索这些神经保护剂的潜力。我们的研究可能最终导致帕金森病预防性治疗策略的发展。与公共健康相关：吸烟或喝咖啡的人患帕金森氏症(PD)的频率比普通公众低得多。这些发现让我们假设，烟草和咖啡中含有能够预防帕金森氏症的化学物质。我们将使用两种不同的帕金森病苍蝇模型来验证这一假说，并确定烟草和咖啡中负责保护的特定化学制剂。我们的研究可能最终导致帕金森病预防性治疗策略的发展。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common and highly debilitating movement disorder caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms responsible for PD pathogenesis are poorly understood, and there are currently no preventative treatments for this disorder. Epidemiological studies aimed at the identification of environmental factors that influence the incidence of PD have provided overwhelming data in support of a substantially reduced risk of PD among coffee and tobacco users. While there are several possible interpretations of these findings, we hypothesize that tobacco and coffee contain chemicals that confer neuroprotection. To test this hypothesis we have been using two different Drosophila models of PD. Specifically, the two PD models that we have been using in our work include a fly strain bearing a null allele of the parkin gene, and a transgenic fly strain overexpressing the human 1-synuclein protein. Both of our fly models exhibit multiple characteristics of PD, most notably, selective degeneration of dopaminergic neurons in the central nervous system. In preliminary studies we have used our fly PD models to test the neuroprotective potential of tobacco and coffee extracts and to compare the neuroprotective effects of these extracts to nicotine and caffeine, the suspected neuroprotective agents of tobacco and coffee, respectively. Our studies indicate that coffee and tobacco are indeed neuroprotective in both of our fly models. However, nicotine and caffeine alone do not appear to confer neuroprotection, suggesting that the neuroprotective components of tobacco and coffee are novel chemical species. There are two major aims of the current application: the first aim involves identification and structural characterization of the neuroprotective components of tobacco and coffee; the second aim involves experiments to define the mechanism by which tobacco and coffee confer neuroprotection. Drosophila is ideal for these studies because the short generation time, powerful genetic tools, and evolutionary conservation of neurodegenerative disease mechanisms in this organism will allow us to quickly and efficiently explore the potential of these neuroprotective agents in a fashion that should be pertinent to humans. Our studies could ultimately lead to the development of preventative treatment strategies for PD. PUBLIC HEALTH RELEVANCE: People who smoke or drink coffee develop Parkinson's disease (PD) at a significantly lower frequency than the general public. These findings lead us to hypothesize that tobacco and coffee contain chemicals that confer protection from developing PD. We will use two different fly models of PD to test this hypothesis and to identify the specific chemical agents in tobacco and coffee that are responsible for protection. Our studies could ultimately lead to the development of preventative treatment strategies for PD.