Division of Life and Pharmaceutical Sciences, College of Pharmacy, Brain Disease Research Institute, Ewha Woman's University, Seoul, South Korea.
J Neurochem. 2010 Jan;112(2):366-76. doi: 10.1111/j.1471-4159.2009.06463.x. Epub 2009 Oct 29.
Our previous microarray analysis identified a neuroprotective protein Oxi-alpha, that was down-regulated during oxidative stress (OS)-induced cell death in dopamine neurons [Neurochem. Res. (2004) vol. 29, pp. 1223]. Here we find that the phylogenetically conserved Oxi-alpha protects against OS by a novel mechanism: activation of the mammalian target of rapamycin (mTOR) kinase and subsequent repression of autophagic vacuole accumulation and cell death. To the best of our knowledge, Oxi-alpha is the first molecule discovered in dopamine neurons, which activates mTOR kinase. Indeed, the down-regulation of Oxi-alpha by OS suppresses the activation of mTOR kinase. The pathogenic effect of down-regulated Oxi-alpha was confirmed by gene-specific knockdown experiment, which resulted in not only the repression of mTOR kinase and the subsequent phosphorylation of p70 S6 kinase and 4E-BP1, but also enhanced susceptibility to OS. In accordance with these observations, treatment with rapamycin, an mTOR inhibitor and autophagy inducer, potentiated OS-induced cell death, while similar treatment with an autophagy inhibitor, 3-methyladenine protected the dopamine cells. Our findings present evidence for the presence of a novel class of molecule involved in autophagic cell death triggered by OS in dopamine neurons.
我们之前的基因芯片分析鉴定了一种神经保护蛋白 Oxi-alpha，它在多巴胺神经元的氧化应激（OS）诱导的细胞死亡过程中下调。在这里，我们发现进化保守的 Oxi-alpha 通过一种新的机制来抵抗 OS：激活哺乳动物雷帕霉素靶蛋白（mTOR）激酶，随后抑制自噬空泡的积累和细胞死亡。据我们所知，Oxi-alpha 是在多巴胺神经元中发现的第一个激活 mTOR 激酶的分子。事实上，OS 下调 Oxi-alpha 会抑制 mTOR 激酶的激活。通过基因特异性敲低实验证实了下调的 Oxi-alpha 的致病作用，这不仅抑制了 mTOR 激酶及其随后的 p70 S6 激酶和 4E-BP1 的磷酸化，还增强了对 OS 的易感性。与这些观察结果一致，mTOR 抑制剂和自噬诱导剂雷帕霉素的处理增强了 OS 诱导的细胞死亡，而类似的自噬抑制剂 3-甲基腺嘌呤则保护多巴胺细胞。我们的研究结果为 OS 在多巴胺神经元中诱导的自噬性细胞死亡中存在一类新的分子提供了证据。
