Bacterial neurotoxicity as an environmental model for Parkinson disease

描述(由申请人提供)：神经退行性疾病，如帕金森病(PD)，是一个主要的社会负担，随着我们平均人口老龄化，发病率不断增加。最近的研究表明，不同种类的链霉菌能够产生一种神经毒性代谢物，导致线虫模式生物秀丽线虫和人SH-SY5Y神经母细胞瘤细胞的多巴胺能退化。这些细菌通常在土壤环境中发现，接触它们的排泄物可能是帕金森病的一个贡献者，而帕金森病在农村生活方式的个人中更普遍。虽然接触杀虫剂可能是部分责任，但这些本身并不能解释帕金森病的流行，即使在农村地区也是如此。这项R15提案利用线虫作为评分多巴胺(DA)神经元变性的主要测试系统，以探索链霉菌诱导神经变性的机制。虽然长期暴露于有毒代谢物会导致DA神经退化，但将进行实验以确定急性暴露范例是否也会导致神经退化(目标I)。已建立的突变和转基因虫株将被用来研究是否在与帕金森病相关的不同遗传背景下观察到差异性退化(AIM II)。与神经退行性变相关的细胞通路，如细胞凋亡、DA代谢和线粒体功能，也将在暴露于代谢物后进行评估(AIM III)。最后，将在人类神经细胞培养中进行研究，以验证从无脊椎动物系统收集的结果，并扩展证明链霉菌代谢物的神经毒性活性延伸到这些培养物的数据(目标IV)。综上所述，这些研究代表了一种综合策略，以快速识别这种新的环境因素的意义及其对神经退行性变的影响，因为它与帕金森病有关。除了对研究生和本科生的培训和指导之外，这项提议还包括对农村人口健康差距的一个可能原因的理解。 公共卫生意义：帕金森氏病(PD)是最常见的运动障碍，影响着100多万美国人，但这种神经退行性疾病的潜在原因在很大程度上仍未得到医学科学的证实。这项建议旨在通过调查暴露于常见土壤细菌产生的有毒化合物的可能性来解决尚未解决的挑战，即识别导致帕金森病的环境因素，以增强在衰老过程中对神经退化的易感性。通过涉及以学生为中心的研究的综合培训和实验策略，将使用完整的动物模型系统以及人类细胞培养实验来探索潜在的神经毒性机制，由此产生的结果可能包括建立一个新的范式来理解神经退行性变，这可能有助于开发模型来推进诊断和治疗策略，以对抗帕金森病。

DESCRIPTION (provided by applicant): Neurodegenerative diseases such as Parkinson disease (PD) comprise a major societal burden with increasing occurrence as our mean population ages. Recent studies have demonstrated that bacteria of distinct Streptomyces species have the capacity to produce a neurotoxic metabolite that causes dopaminergic degeneration in the nematode model organism C. elegans and in human SH-SY5Y neuroblastoma cells. These bacteria are commonly found in soil environments and exposure to their excretions may be a contributor to PD, which is more prevalent in individuals with a rural lifestyle. While exposures to pesticides may be a partially responsible, these alone cannot account for prevalence of PD, even in rural areas. This R15 proposal utilizes C. elegans as a primary assay system for scoring dopamine (DA) neuron degeneration to explore mechanisms involved in Streptomyces-induced neurodegeneration. While chronic exposures to the toxic metabolite cause DA neurodegeneration, experiments will be performed to determine if acute exposure paradigms also result in neurodegeneration (Aim I). Established mutant and transgenic worm strains will be utilized to investigate whether differential degeneration is observed in distinct genetic backgrounds related to PD (Aim II). Cellular pathways associated with neurodegeneration, such as apoptosis, DA metabolism and mitochondrial function will also be assessed following exposure to the metabolite (Aim III). Finally, studies in human neuronal cell cultures will be conducted, both to validate results gleaned from the invertebrate system and to expand upon data demonstrating that the neurotoxic activity of the Streptomyces metabolite extends to these cultures (Aim IV). Taken together, these studies represent an integrated strategy to rapidly discern the significance of this novel environmental factor and its influence on neurodegeneration as it pertains to PD. Included among the broader impacts of this proposal are an understanding of one possible cause of health disparities in rural populations, in addition to training and mentorship of graduate and undergraduate students. PUBLIC HEALTH RELEVANCE: Parkinson's Disease (PD) is the most common movement disorder affecting over 1 million Americans, yet underlying causes of this neurodegenerative disease have largely eluded medical science. This proposal is designed to address an unmet challenge of discerning environmental factors that contribute to PD by investigating the potential for exposures to a toxic compound produced by common soil bacteria to enhance susceptibility to neurodegeneration over the course of aging. Through an integrated training and experimental strategy involving student-centered research, mechanisms underlying neurotoxicity will be explored using a whole animal model system, as well as human cell culture experiments, whereby outcomes include potentially establishing a new paradigm for understanding neurodegeneration that may aid in the development of models to advance diagnostic and therapeutic strategies to combat PD.