Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model.
Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model.
复制标题
DOI：
10.1038/cddis.2013.513
复制
发表时间：
2014-01-09
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
帕金森病 (PD) 的遗传性和特发性形式的特征是多巴胺 (DA) 神经元的丧失，并且通常形成含有 α-突触核蛋白 (α-syn) 蛋白的蛋白质内含物。导致帕金森病的环境因素在很大程度上尚未解决，但百草枯或鱼藤酮等毒素是经过充分研究的易感性增强剂。此前，我们报道了委内瑞拉链霉菌产生的细菌代谢产物引起了秀丽隐杆线虫和人类 SH-SY5Y 神经元的年龄和剂量依赖性 DA 神经变性。我们假设这种来自常见土壤细菌的代谢物与帕金森病易感性基因突变或毒物结合可能会加剧神经变性。在这里，我们报告说，暴露于表达人类 α-syn 或 LRRK2 G2019S 的线虫 DA 神经元中的代谢物会加剧神经变性。使用 PD 毒素模型 6-羟基多巴胺和鱼藤酮，我们证明暴露于一种以上环境风险因素对引发 DA 神经变性具有累加效应。有证据表明，PD 相关毒物会导致线粒体功能障碍，因此我们研究了代谢物对线粒体活性和氧化应激的影响。对秀丽隐杆线虫提取物的离体测定表明，这种代谢物会导致活性氧的过量产生。同样，在体内观察到超氧化物歧化酶报告基因的表达增强。抗氧化剂普罗布考也完全挽救了代谢物引起的 DA 神经变性。有趣的是，应激反应性 FOXO 转录因子 DAF-16 在接触代谢物后被激活。通过进一步的机制分析，我们发现与代谢物暴露相关的线粒体缺陷包括三磷酸腺苷损伤和线粒体未折叠蛋白反应的上调。复合物 I 激活剂可以缓解代谢物诱导的 DA 神经元毒性。 RNA 干扰 (RNAi) 敲低线粒体复合物 I 亚基可挽救 DA 神经元代谢物诱导的毒性。综上所述，我们对委内瑞拉链球菌代谢物的细胞反应的表征表明，这种假定的神经毒性环境触发因素可能部分通过线粒体功能障碍和氧化应激导致细胞死亡。
Genetic and idiopathic forms of Parkinson's disease (PD) are characterized by loss of dopamine (DA) neurons and typically the formation of protein inclusions containing the alpha-synuclein (α-syn) protein. Environmental contributors to PD remain largely unresolved but toxins, such as paraquat or rotenone, represent well-studied enhancers of susceptibility. Previously, we reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. We hypothesized that this metabolite from a common soil bacterium could enhance neurodegeneration in combination with PD susceptibility gene mutations or toxicants. Here, we report that exposure to the metabolite in C. elegans DA neurons expressing human α-syn or LRRK2 G2019S exacerbates neurodegeneration. Using the PD toxin models 6-hydroxydopamine and rotenone, we demonstrate that exposure to more than one environmental risk factor has an additive effect in eliciting DA neurodegeneration. Evidence suggests that PD-related toxicants cause mitochondrial dysfunction, thus we examined the impact of the metabolite on mitochondrial activity and oxidative stress. An ex vivo assay of C. elegans extracts revealed that this metabolite causes excessive production of reactive oxygen species. Likewise, enhanced expression of a superoxide dismutase reporter was observed in vivo. The anti-oxidant probucol fully rescued metabolite-induced DA neurodegeneration, as well. Interestingly, the stress-responsive FOXO transcription factor DAF-16 was activated following exposure to the metabolite. Through further mechanistic analysis, we discerned the mitochondrial defects associated with metabolite exposure included adenosine triphosphate impairment and upregulation of the mitochondrial unfolded protein response. Metabolite-induced toxicity in DA neurons was rescued by complex I activators. RNA interference (RNAi) knockdown of mitochondrial complex I subunits resulted in rescue of metabolite-induced toxicity in DA neurons. Taken together, our characterization of cellular responses to the S. venezuelae metabolite indicates that this putative environmental trigger of neurotoxicity may cause cell death, in part, through mitochondrial dysfunction and oxidative stress.
登录
查看更多内容
DOI：
10.1042/bss0660085
发表时间：
1999-01-01
期刊：
MITOCHONDRIA AND CELL DEATH
影响因子：
--
作者：
Greenamyre, JT;MacKenzie, G;Stephans, SE
通讯作者：
Stephans, SE
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
4.7
作者：
Höglinger, GU;Carrard, G;Hirsch, EC
通讯作者：
Hirsch, EC
影响因子：
4
作者：
Haynes, Cole M.;Ron, David
通讯作者：
Ron, David
影响因子：
3.5
作者：
Grad, LI;Lemire, BD
通讯作者：
Lemire, BD