Bacterial neurotoxicity as an environmental model for Parkinson disease

细菌神经毒性作为帕金森病的环境模型

• 批准号: 8093956
• 负责人: Kim A Caldwell
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093956
• 关键词: Accounting; Actinomycetales; Acute; Address; Aerobic; Affect; Age; Aging; American; Animal Model; Animals; Apoptosis; Bacteria; Biological Assay; Biological Models; Caenorhabditis elegans; Cell Culture Techniques; Cell Death; Cell Line; Cell model; Cell physiology; Cessation of life; Chronic; Data; Diagnostic; Disease; Disease Progression; Dopamine; Dose; Environment; Environmental Exposure; Environmental Risk Factor; Excretory function; Exposure to; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Glean; Grant; High Prevalence; Human; Human Genetics; Individual; Invertebrates; Investigation; Iron Chelation; Life Style; Medical; Mentorship; Metabolism; Mitochondria; Modeling; Movement Disorders; Nature; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Pesticides; Physiologic pulse; Play; Poison; Population; Predisposition; Prevalence; Process; Production; Proteasome Inhibition; Proteasome Inhibitor; Proteins; RNA Interference; Research; Role; Rural; Rural Population; Science; Soil; Streptomyces; Students; System; Testing; Therapeutic; Time; Toxic Environmental Substances; Toxin; Training; Transgenic Organisms; Ubiquitin; Validation; Work; Xenobiotic Metabolism; Yeasts; combat; design; dopaminergic neuron; genetic effector; health disparity; model development; multicatalytic endopeptidase complex; mutant; nervous system disorder; neuroblastoma cell; neuron loss; neurotoxic; neurotoxicity; novel; oxidative damage; prospective; protein folding; research study; response; rural area

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.

描述（由申请人提供）：神经退行性疾病，如帕金森病（PD）构成了一个主要的社会负担，随着我们的平均人口老龄化，发病率越来越高。最近的研究表明，不同链霉菌种类的细菌有能力产生一种神经毒性代谢物，导致线虫模式生物秀丽隐杆线虫和人类SH-SY5Y神经母细胞瘤细胞的多巴胺能变性。这些细菌通常存在于土壤环境中，接触它们的排泄物可能会导致PD，而PD在农村生活方式的人群中更为普遍。虽然接触农药可能是部分原因，但仅凭农药并不能解释帕金森病的流行，即使在农村地区也是如此。该R15提案利用秀丽隐杆线虫作为评分多巴胺（DA）神经元变性的主要检测系统，以探索链霉菌诱导的神经变性的机制。虽然慢性暴露于有毒代谢物会导致DA神经变性，但将进行实验以确定急性暴露模式是否也会导致神经变性（Aim I）。将利用已建立的突变和转基因蠕虫菌株来研究是否在与PD相关的不同遗传背景中观察到差异变性（Aim II）。暴露于代谢物后，还将评估与神经退行性变相关的细胞通路，如凋亡、DA代谢和线粒体功能（Aim III）。最后，将进行人类神经元细胞培养的研究，以验证从无脊椎动物系统收集的结果，并扩展数据，证明链霉菌代谢物的神经毒性活性延伸到这些培养物（Aim IV）。综上所述，这些研究代表了一种综合策略，可以快速识别这种新型环境因素的重要性及其对PD相关神经退行性疾病的影响。这项建议的更广泛影响包括了解农村人口健康差异的一个可能原因，以及对研究生和本科生的培训和指导。

项目成果

Phenazine derivatives cause proteotoxicity and stress in C. elegans.

• DOI: 10.1016/j.neulet.2014.09.055
• 发表时间: 2015-01-01
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Ray A;Rentas C;Caldwell GA;Caldwell KA
• 通讯作者: Caldwell KA

A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.

• DOI: 10.1038/cddis.2015.270
• 发表时间: 2015-10-15
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Martinez BA;Kim H;Ray A;Caldwell GA;Caldwell KA
• 通讯作者: Caldwell KA

Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model.

• DOI: 10.1038/cddis.2013.513
• 发表时间: 2014-01-09
• 期刊: Cell death & disease
• 影响因子: 9