The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity.
The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity.
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DOI：
10.1523/jneurosci.5303-08.2009
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发表时间：
2009-01-14
期刊：
影响因子：
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通讯作者：
Bernier G
中科院分区：
文献类型：
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作者：
Chatoo W;Abdouh M;David J;Champagne MP;Ferreira J;Rodier F;Bernier G
衰老可以通过遗传程序和/或通过分子损伤的累积速率来确定。由线粒体代谢产生的活性氧（ROS）被认为是分子损伤的中心来源，并且细胞内ROS水平与抗氧化防御之间的不平衡是衰老脑的特征。然而，人们对衰老如何改变自由基浓度并增加发展大多数神经退行性疾病的风险知之甚少。在这里，我们表明，Polycomb组和癌基因Bmi 1是必需的神经元抑制细胞凋亡和诱导的过早衰老样程序的特点是减少抗氧化防御。在断奶前，Bmi 1 −/−小鼠表现出类似于早衰症的眼部和脑部表型，而Bmi 1 +/−小鼠虽然表面上正常，但寿命缩短。神经元中Bmi 1缺乏导致p19 Arf/p53水平增加、异常高的ROS浓度和对神经毒性剂的超敏反应。大多数Bmi 1对神经元氧化代谢的功能在遗传上与p53促氧化活性的抑制有关，p53促氧化活性也在生理条件下起作用。在Bmi 1 −/−神经元中，p53和辅助阻遏物在抗氧化基因启动子处积累，与抑制的染色质状态和抗氧化基因下调相关。这些发现提供了一种分子机制，解释了Bmi 1如何调节自由基浓度，并揭示了Bmi 1缺乏对神经元存活和衰老的生物学影响。
Aging may be determined by a genetic program and/or by the accumulation rate of molecular damages. Reactive oxygen species (ROS) generated by the mitochondrial metabolism have been postulated to be the central source of molecular damages and imbalance between levels of intracellular ROS and antioxidant defenses is a characteristic of the aging brain. How aging modifies free radicals concentrations and increases the risk to develop most neurodegenerative diseases is poorly understood, however. Here we show that the Polycomb group and oncogene Bmi1 is required in neurons to suppress apoptosis and the induction of a premature aging-like program characterized by reduced antioxidant defenses. Before weaning, Bmi1−/− mice display a progeroid-like ocular and brain phenotype while Bmi1+/− mice, although apparently normal, have reduced lifespan. Bmi1 deficiency in neurons results in increased p19Arf/p53 levels, abnormally high ROS concentrations and hypersensitivity to neurotoxic agents. Most Bmi1 functions on neurons oxidative metabolism are genetically linked to repression of p53 pro-oxidant activity, which also operates in physiological conditions. In Bmi1−/− neurons, p53 and co-repressors accumulate at antioxidant gene promoters, correlating with a repressed chromatin state and antioxidant genes downregulation. These findings provide a molecular mechanism explaining how Bmi1 regulates free radical concentrations and reveal the biological impact of Bmi1 deficiency on neuronal survival and aging.