Autophagy is a protective response to ethanol neurotoxicity
Autophagy is a protective response to ethanol neurotoxicity
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DOI：
10.4161/auto.21376
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发表时间：
2012-11-01
期刊：
影响因子：
13.3
通讯作者：
Luo, Jia
中科院分区：
文献类型：
--
作者：
Chen, Gang;Ke, Zunji;Luo, Jia
乙醇是一种神经致畸剂，神经变性是发育暴露于乙醇的最具破坏性的后果。乙醇引起的神经退行性变的机制是复杂的。乙醇暴露产生活性氧（ROS），导致大脑中的氧化应激。我们假设，乙醇会激活自噬，以减轻氧化应激和神经毒性。我们的研究结果表明，乙醇增加了自噬标志物Map 1 lc 3-II（LC 3-II）的水平和上调LC 3斑点在SH-SY 5 Y神经母细胞瘤细胞。它还提高了发育中大脑中LC 3-II和BECN 1的水平;同时，乙醇降低了SQSTM 1（p62）的水平。巴弗洛霉素A1，自噬体和溶酶体融合的抑制剂，增加p62水平在乙醇的存在下。巴弗洛霉素A1和雷帕霉素增强乙醇增加的LC 3脂化，而渥曼青霉素和BECN 1特异性shRNA抑制乙醇促进的LC 3脂化。乙醇增加了线粒体自噬，这也受到BECN 1 shRNA和雷帕霉素的调节。有证据表明，乙醇促进自噬通量。在体外和发育中的大脑中，雷帕霉素激活自噬减少了乙醇诱导的ROS产生，改善了乙醇诱导的神经元死亡，而渥曼青霉素和BECN 1特异性shRNA抑制自噬增强了乙醇诱导的ROS产生，加剧了乙醇的神经毒性。此外，乙醇抑制MTOR通路，下调MTOR提供神经保护。总之，结果表明，自噬激活是一种神经保护反应，以减轻乙醇毒性。乙醇对自噬活性的调节可能由MTOR途径介导。
Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. The mechanisms underlying ethanol-induced neurodegeneration are complex. Ethanol exposure produces reactive oxygen species (ROS) which cause oxidative stress in the brain. We hypothesized that ethanol would activate autophagy to alleviate oxidative stress and neurotoxicity. Our results indicated that ethanol increased the level of the autophagic marker Map1lc3-II (LC3-II) and upregulated LC3 puncta in SH-SY5Y neuroblastoma cells. It also enhanced the levels of LC3-II and BECN1 in the developing brain; meanwhile, ethanol reduced SQSTM1 (p62) levels. Bafilomycin A 1, an inhibitor of autophagosome and lysosome fusion, increased p62 levels in the presence of ethanol. Bafilomycin A 1 and rapamycin potentiated ethanol-increased LC3 lipidation, whereas wortmannin and a BECN1-specific shRNA inhibited ethanol-promoted LC3 lipidation. Ethanol increased mitophagy, which was also modulated by BECN1 shRNA and rapamycin. The evidence suggested that ethanol promoted autophagic flux. Activation of autophagy by rapamycin reduced ethanol-induced ROS generation and ameliorated ethanol-induced neuronal death in vitro and in the developing brain, whereas inhibition of autophagy by wortmannin and BECN1-specific shRNA potentiated ethanol-induced ROS production and exacerbated ethanol neurotoxicity. Furthermore, ethanol inhibited the MTOR pathway and downregulation of MTOR offered neuroprotection. Taken together, the results suggest that autophagy activation is a neuroprotective response to alleviate ethanol toxicity. Ethanol modulation of autophagic activity may be mediated by the MTOR pathway.