Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy
Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy
复制标题
柴油机尾气提取物暴露通过破坏自噬诱导神经元毒性
DOI：
10.1093/toxsci/kfaa055
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发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Bronstein, Jeff M.
中科院分区：
文献类型：
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作者：
Barnhill, Lisa M.;Khuansuwan, Sataree;Bronstein, Jeff M.
绝大多数神经退行性疾病不能单独归因于遗传原因，因此，人们对确定疾病风险的环境修饰因素非常感兴趣。流行病学研究支持长期接触空气污染物与疾病风险之间存在关联。在这里，我们研究的机制，柴油废气，空气污染的主要组成部分，诱导神经毒性。使用斑马鱼模型，我们发现暴露于柴油机尾气颗粒提取物会导致行为缺陷和神经元数量的显着减少。神经毒性至少部分是由于自噬通量减少，自噬通量是涉及神经变性的主要途径。这种神经元损失伴随着易于聚集的神经元蛋白的增加而发生。此外，通过与诱导自噬的药物尼罗替尼共同处理，可以减轻柴油尾气颗粒提取物对斑马鱼的神经毒性。本研究将环境暴露与体内模型系统中的蛋白质平衡改变联系起来。这些结果揭示了为什么长期暴露于交通相关的空气污染会增加神经退行性疾病的风险，并为探索减轻环境暴露和促进神经保护的疗法开辟了新的途径。
The vast majority of neurodegenerative disease cannot be attributed to genetic causes alone and as a result, there is significant interest in identifying environmental modifiers of disease risk. Epidemiological studies have supported an association between long-term exposure to air pollutants and disease risk. Here, we investigate the mechanisms by which diesel exhaust, a major component of air pollution, induces neurotoxicity. Using a zebrafish model, we found that exposure to diesel exhaust particulate extract caused behavioral deficits and a significant decrease in neuron number. The neurotoxicity was due, at least in part, to reduced autophagic flux, which is a major pathway implicated in neurodegeneration. This neuron loss occurred alongside an increase in aggregation-prone neuronal protein. Additionally, the neurotoxicity induced by diesel exhaust particulate extract in zebrafish was mitigated by co-treatment with the autophagy-inducing drug nilotinib. This study links environmental exposure to altered proteostasis in an in vivo model system. These results shed light on why long-term exposure to traffic-related air pollution increases neurodegenerative disease risk and open up new avenues for exploring therapies to mitigate environmental exposures and promote neuroprotection.