Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-05-31 , DOI: 10.1007/s10565-021-09618-9 M Saeid Jami 1 , Hiromi Murata 2 , Lisa M Barnhill 1, 2 , Sharon Li 1 , Jeff M Bronstein 1, 2
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Neurodegenerative diseases are a major cause of disability in the world, but their etiologies largely remain elusive. Genetic factors can only account for a minority of risk for most of these disorders, suggesting environmental factors play a significant role in the development of these diseases. Prolonged exposure to air pollution has recently been identified to increase the risk of Alzheimer’s and Parkinson’s diseases, but the molecular mechanisms by which it acts are not well understood. Zebrafish embryos exposed to diesel exhaust particle extract (DEPe) lead to dysfunctional autophagy and neuronal loss. Here, we exposed zebrafish embryos to DEPe and performed high throughput proteomic and transcriptomic expression analyses from their brains to identify pathogenic pathways induced by air pollution. DEPe treatment altered several biological processes and signaling pathways relevant to neurodegenerative processes, including xenobiotic metabolism, phagosome maturation, and amyloid processing. The biggest induction of gene expression in brains was in Cyp1A (over 30-fold). The relevance of this expression change was confirmed by blocking induction using CRISPR/Cas9, which resulted in a dramatic increase in sensitivity to DEPe toxicity, confirming that Cyp1A induction was a compensatory protective mechanism. These studies identified disrupted molecular pathways that may contribute to the pathogenesis of neurodegenerative disorders. Ultimately, determining the molecular basis of how air pollution increases the risk of neurodegeneration will help in the development of disease-modifying therapies.
Graphical abstract
中文翻译：
柴油机尾气暴露改变了斑马鱼大脑中与神经退行性变有关的网络的表达
神经退行性疾病是世界上导致残疾的主要原因，但其病因在很大程度上仍然难以捉摸。遗传因素只能解释大多数这些疾病的一小部分风险，这表明环境因素在这些疾病的发展中发挥着重要作用。最近发现，长期暴露在空气污染中会增加患阿尔茨海默病和帕金森病的风险，但其作用的分子机制尚不清楚。暴露于柴油机尾气颗粒提取物 (DEPe) 的斑马鱼胚胎会导致自噬功能失调和神经元损失。在这里，我们将斑马鱼胚胎暴露于 DEPe 中，并对斑马鱼的大脑进行高通量蛋白质组和转录组表达分析，以确定空气污染引起的致病途径。DEPe 治疗改变了与神经退行性过程相关的多种生物过程和信号通路，包括异生物质代谢、吞噬体成熟和淀粉样蛋白加工。大脑中最大的基因表达诱导是 Cyp1A（超过 30 倍）。通过使用 CRISPR/Cas9 阻断诱导，证实了这种表达变化的相关性，这导致对 DEPe 毒性的敏感性急剧增加，证实了 Cyp1A 诱导是一种补偿性保护机制。这些研究发现了可能导致神经退行性疾病发病机制的分子途径被破坏。最终，确定空气污染如何增加神经退行性变风险的分子基础将有助于开发缓解疾病的疗法。
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