Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.
Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.
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DOI：
10.1371/journal.pone.0007227
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发表时间：
2009-10-06
期刊：
影响因子：
3.7
通讯作者：
Caldwell GA
中科院分区：
文献类型：
--
作者：
Caldwell KA;Tucci ML;Armagost J;Hodges TW;Chen J;Memon SB;Blalock JE;DeLeon SM;Findlay RH;Ruan Q;Webber PJ;Standaert DG;Olson JB;Caldwell GA
帕金森病（PD）涉及进行性神经变性，包括来自黑质的多巴胺（DA）神经元的损失。选择与罕见家族性PD在细胞通路中功能相关的基因，如参与蛋白质降解的泛素-蛋白酶体系统（UPS）。蛋白质（如α-突触核蛋白）的错误折叠和积累形成称为路易体的包涵体代表了PD的临床标志。鉴于散发性PD在患者人群中占主导地位，环境毒素可能诱发疾病，尽管其性质在很大程度上尚不清楚。因此，一个未满足的挑战围绕着发现因果或贡献的神经毒性因素，可以解释散发性PD的患病率。放线菌目中的细菌以其强大的次级代谢产物生产而闻名，可能是未知的环境暴露源。其中，需氧菌属，链霉菌，产生天然的蛋白酶体抑制剂，阻止蛋白质降解，并可能损害DA神经元。在这里，我们证明了一种常见的土壤细菌，S。委内瑞拉，造成DA神经变性的线虫，秀丽隐杆线虫，这增加了动物的年龄。这种破坏UPS功能的代谢物导致所有检查的神经元类别逐渐变性，但DA神经元特别容易受到暴露。DA的存在加剧了毒性，因为神经变性减弱突变体线虫耗尽酪氨酸羟化酶（TH），在DA生产的限速酶。引人注目的是，该因子导致人SH-SY 5 Y神经母细胞瘤细胞（一种多巴胺能细胞系）的剂量依赖性死亡。纯化毒性活性的努力表明，它是一种高度稳定、亲脂性和化学独特的小分子。一个强大的神经毒性因子，选择性地影响神经元的生存，在一个渐进的，但温和的方式是一致的年龄相关的神经退行性疾病的病因学的证据。总的来说，这些数据表明，暴露于特定常见土壤细菌的代谢产物可能是PD的一个环境因素。
Parkinson disease (PD) involves progressive neurodegeneration, including loss of dopamine (DA) neurons from the substantia nigra. Select genes associated with rare familial forms of PD function in cellular pathways, such as the ubiquitin-proteasome system (UPS), involved in protein degradation. The misfolding and accumulation of proteins, such as α-synuclein, into inclusions termed Lewy Bodies represents a clinical hallmark of PD. Given the predominance of sporadic PD among patient populations, environmental toxins may induce the disease, although their nature is largely unknown. Thus, an unmet challenge surrounds the discovery of causal or contributory neurotoxic factors that could account for the prevalence of sporadic PD. Bacteria within the order Actinomycetales are renowned for their robust production of secondary metabolites and might represent unidentified sources of environmental exposures. Among these, the aerobic genera, Streptomyces, produce natural proteasome inhibitors that block protein degradation and may potentially damage DA neurons. Here we demonstrate that a metabolite produced by a common soil bacterium, S. venezuelae, caused DA neurodegeneration in the nematode, Caenorhabditis elegans, which increased as animals aged. This metabolite, which disrupts UPS function, caused gradual degeneration of all neuronal classes examined, however DA neurons were particularly vulnerable to exposure. The presence of DA exacerbated toxicity because neurodegeneration was attenuated in mutant nematodes depleted for tyrosine hydroxylase (TH), the rate-limiting enzyme in DA production. Strikingly, this factor caused dose-dependent death of human SH-SY5Y neuroblastoma cells, a dopaminergic line. Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule. Evidence of a robust neurotoxic factor that selectively impacts neuronal survival in a progressive yet moderate manner is consistent with the etiology of age-associated neurodegenerative diseases. Collectively, these data suggest the potential for exposures to the metabolites of specific common soil bacteria to possibly represent a contributory environmental component to PD.
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影响因子：
--
作者：
Firestone, JA;Smith-Weller, T;Checkoway, H
通讯作者：
Checkoway, H
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
DOI：
10.1016/j.bbadis.2009.01.012
发表时间：
2009-07
影响因子：
6.2
作者：
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通讯作者：
Petrucelli, Leonard
DOI：
10.1097/nen.0b013e318186de64
发表时间：
2008-10-01
影响因子：
3.2
作者：
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通讯作者：
Le, Weidong
影响因子：
3.8
作者：
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通讯作者：
LeWitt, PA