No Country for Old Worms: A Systematic Review of the Application of C. elegans to Investigate a Bacterial Source of Environmental Neurotoxicity in Parkinson's Disease.
No Country for Old Worms: A Systematic Review of the Application of C. elegans to Investigate a Bacterial Source of Environmental Neurotoxicity in Parkinson's Disease.
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DOI：
10.3390/metabo8040070
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发表时间：
2018-10-29
期刊：
影响因子：
4.1
通讯作者：
Caldwell GA
中科院分区：
文献类型：
--
作者：
Caldwell KA;Thies JL;Caldwell GA
虽然在识别与帕金森病（PD）的遗传关联方面取得了进展，但识别难以捉摸的环境因素需要应用非常规假设和实验策略。在这里，我们提供了一个概述的研究，我们进行了一种常见的土壤细菌，委内瑞拉链霉菌（S。Ven），表明该细菌显示的毒性在多种细胞机制中引起应激，例如泛素蛋白酶体系统和线粒体稳态。这种功能障碍最终导致秀丽隐杆线虫的年龄和剂量依赖性神经变性。值得注意的是，多巴胺能神经元具有高度的易感性，但所有的神经元类别最终在暴露后退化。毒性进一步延伸至人SH-SY 5 Y细胞，其也在暴露后退化。此外，表达异源聚集倾向蛋白的线虫的神经元显示增强的代谢物脆弱性。这些机制分析共同揭示了这种细菌源性神经毒素的独特代谢组学指纹。在考虑到流行病学的差异在地方影响PD的发病率，我们调查了土壤从不同地区的亚拉巴马，发现暴露于约30%的分离的链霉菌属物种造成蠕虫多巴胺能神经元死亡。除了衰老之外，PD的少数几个既定因素之一似乎是农村生活方式，定期暴露于土壤可能会增加与产生此类毒素的细菌相互作用的风险。总之，这些数据表明，链霉菌属内的一种新型毒物可能是与PD相关的进行性神经变性的环境因素。
While progress has been made in discerning genetic associations with Parkinson’s disease (PD), identifying elusive environmental contributors necessitates the application of unconventional hypotheses and experimental strategies. Here, we provide an overview of studies that we conducted on a neurotoxic metabolite produced by a species of common soil bacteria, Streptomyces venezuelae (S. ven), indicating that the toxicity displayed by this bacterium causes stress in diverse cellular mechanisms, such as the ubiquitin proteasome system and mitochondrial homeostasis. This dysfunction eventually leads to age and dose-dependent neurodegeneration in the nematode Caenorhabditis elegans. Notably, dopaminergic neurons have heightened susceptibility, but all of the neuronal classes eventually degenerate following exposure. Toxicity further extends to human SH-SY5Y cells, which also degenerate following exposure. Additionally, the neurons of nematodes expressing heterologous aggregation-prone proteins display enhanced metabolite vulnerability. These mechanistic analyses collectively reveal a unique metabolomic fingerprint for this bacterially-derived neurotoxin. In considering that epidemiological distinctions in locales influence the incidence of PD, we surveyed soils from diverse regions of Alabama, and found that exposure to ~30% of isolated Streptomyces species caused worm dopaminergic neurons to die. In addition to aging, one of the few established contributors to PD appears to be a rural lifestyle, where exposure to soil on a regular basis might increase the risk of interaction with bacteria producing such toxins. Taken together, these data suggest that a novel toxicant within the Streptomyces genus might represent an environmental contributor to the progressive neurodegeneration that is associated with PD.
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影响因子：
4
作者：
Goldwurm, S;Di Fonzo, A;Bonifati, V
通讯作者：
Bonifati, V
影响因子：
--
作者：
Back P;Braeckman BP;Matthijssens F
通讯作者：
Matthijssens F
影响因子：
6.1
作者：
Arnold, Beth;Cassady, Steven J.;VanLaar, Victor S.;Berman, Sarah B.
通讯作者：
Berman, Sarah B.
影响因子：
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作者：
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通讯作者：
Houtkooper RH
影响因子：
11.2
作者：
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通讯作者：
Przedborski, Serge