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首页> 外文期刊>Toxicology and Applied Pharmacology >Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells
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Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells

机译：硫胺素缺乏诱导源自诱导多能干细胞的人神经元的内质网胁迫和氧化应激

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摘要

Thiamine (vitamin BI) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells(hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration-and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2 alpha, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration. (C) 2017 Elsevier Inc. All rights reserved.
机译：硫胺素（维生素BI）缺乏症（TD）在韦尼克脑病（WE）的病因中起着重要作用，WE是一种严重的神经系统疾病。TD在大脑中诱导选择性神经细胞死亡、神经炎症、内质网（ER）应激和氧化应激，这在许多与衰老相关的神经退行性疾病中常见，如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和进行性核上性麻痹（PSP）。然而，潜在的细胞和分子机制仍不清楚。由于缺乏合适的体外模型，这方面的研究进展受阻。人类诱导多能干细胞（hiPSCs）衍生的神经元为药物和环境神经毒性的研究提供了一个相关且有力的工具。在这项研究中，我们首次使用人类诱导的多能干细胞（HIPSC）衍生神经元（iCell神经元）来研究TD诱导的神经退行性变的机制。我们发现TD导致iCell神经元的浓度和持续时间依赖性死亡。TD诱导内质网应激，其表现为内质网应激标记物的增加，如GRP78、XBP-1、CHOP、ATF-6、磷酸化eIF2α和裂解的caspase-12。TD还引发氧化应激，表现为2,4-二硝基苯（DNP）和4-羟基壬烯醛（HNE）的表达增加。内质网应激抑制剂（STF-083010和salubrinal）和抗氧化剂N-乙酰半胱氨酸（NAC）可有效缓解TD诱导的冰盖神经元死亡，支持内质网应激和氧化应激的参与。这表明iCell神经元是研究TD诱导的神经退行性变的细胞和分子机制的新工具。（C） 2017爱思唯尔公司版权所有。

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