A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.
A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.
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DOI：
10.1038/cddis.2015.270
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发表时间：
2015-10-15
影响因子：
9
通讯作者：
Caldwell KA
中科院分区：
文献类型：
--
作者：
Martinez BA;Kim H;Ray A;Caldwell GA;Caldwell KA
基因与环境的相互作用被认为是大多数神经退行性疾病特发性病例的基础。最近，我们报道了从委内瑞拉链霉菌中提取的一种环境代谢产物增加ROS并损伤线粒体，最终导致C.多巴胺能神经元在这里，我们将这些数据与特发性疾病模型联系起来，这些模型预测蛋白质处理的损失是疾病进展的一个组成部分。我们证明，细菌代谢产物导致蛋白质稳定破坏在多个蛋白质错误折叠模型，并有可能协同增强毒性的聚集倾向的蛋白质。在遗传学上，这种代谢物是由pink-1的功能丧失上位调节的，C。线虫PARK 6同源物，负责其他动物系统中的线粒体维护和自噬。此外，代谢物通过类似于泛素蛋白酶体系统（UPS）中功能丧失的遗传途径起作用，我们发现这也是通过PINK-1稳态的丧失来上位调节的。为了确定缓解对抗剂，我们研究了几种已建立的抗氧化剂，发现谷胱甘肽（GSH）可以显着防止代谢物诱导的蛋白质稳态破坏。此外，GSH保护免受MG 132的毒性，并可以补偿pink-1和E3连接酶pdr-1（Parkin同源物）的联合损失。在评估这种代谢物对线粒体维持的影响时，我们观察到它会导致线粒体碎片化，而线粒体碎片化会被GSH减弱，并导致PINK-1依赖性自噬的初始激增。这些研究从机制上推进了我们对神经退行性变的假定环境因素和影响体内神经毒性的因素的理解。
Gene-by-environment interactions are thought to underlie the majority of idiopathic cases of neurodegenerative disease. Recently, we reported that an environmental metabolite extracted from Streptomyces venezuelae increases ROS and damages mitochondria, leading to eventual neurodegeneration of C. elegans dopaminergic neurons. Here we link those data to idiopathic disease models that predict loss of protein handling as a component of disorder progression. We demonstrate that the bacterial metabolite leads to proteostatic disruption in multiple protein-misfolding models and has the potential to synergistically enhance the toxicity of aggregate-prone proteins. Genetically, this metabolite is epistatically regulated by loss-of-function to pink-1, the C. elegans PARK6 homolog responsible for mitochondrial maintenance and autophagy in other animal systems. In addition, the metabolite works through a genetic pathway analogous to loss-of-function in the ubiquitin proteasome system (UPS), which we find is also epistatically regulated by loss of PINK-1 homeostasis. To determine remitting counter agents, we investigated several established antioxidants and found that glutathione (GSH) can significantly protect against metabolite-induced proteostasis disruption. In addition, GSH protects against the toxicity of MG132 and can compensate for the combined loss of both pink-1 and the E3 ligase pdr-1, a Parkin homolog. In assessing the impact of this metabolite on mitochondrial maintenance, we observe that it causes fragmentation of mitochondria that is attenuated by GSH and an initial surge in PINK-1-dependent autophagy. These studies mechanistically advance our understanding of a putative environmental contributor to neurodegeneration and factors influencing in vivo neurotoxicity.