FTO通过c-Jun的脱甲基化促进中风后的神经保护
Anil K Chokkalla1,2, Suresh L Mehta1, Soomin Jeong1,3
1Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
概括
脂肪质量和与肥胖相关的蛋白质 (FTO) 通过减少c-Jun的m6A甲基化来保护中风后的大脑. 这种FTO/m6A/c-Jun通路减少神经元亡和脑损伤,改善功能恢复.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 史诗转录组学 史诗转录组学
背景情况:
- N6-甲基氨酸 (m6A) 调节神经元的功能.
- 大脑缺血会增加m6A水平,因为FTO表达减少.
- 以前的研究表明,AAV9介导的FTO过度表达可以保护中风后的大脑.
研究的目的:
- 阐明FTO依赖神经保护后缺血的机制基础.
- 为了研究m6A脱甲基化在中风恢复中的作用.
- 为了确定FTO在缺血大脑中的关键分子点.
主要方法:
- 在小鼠中的过渡性中脑动脉封闭 (tMCAO) 模型.
- 腺相关病毒9 (AAV9) 对于大脑FTO过度表达.
- 生物信息分析和m6A位点检测在c-Jun.
- 评估蛋白质翻译,亡标志物 (切割caspase-3,TUNEL) 和功能恢复.
主要成果:
- 在不影响转录水平的情况下,FTO过度表达使c-Jun m6A高甲基化正常化.
- 通过FTO介导的m6A脱甲基化抑制了c-Jun的翻译.
- 降低c-Jun水平导致其目标基因的转录抑制.
- 在接受FTO治疗的小鼠中,神经细胞亡和脑损伤的速度减缓.
- 恢复c-Jun水平取消了FTO介导的神经保护和功能恢复.
结论:
- FTO/m6A/c-Jun轴是改善中风后神经元亡和脑损伤的关键途径.
- c-Jun的FTO依赖的m6A脱甲基化促进神经保护和功能恢复.
- 准FTO/m6A/c-Jun通路对于中风治疗具有治疗潜力.
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