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通过失调的eIF4E依赖的翻译控制来控制与自闭症相关的缺陷
Christos G Gkogkas1, Arkady Khoutorsky, Israeli Ran
1Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Nature
|November 23, 2012
概括
细胞翻译启动因子4E结合蛋白2 (4E-BP2) 的失调影响神经蛋白合成,通过改变突触刺激-抑制平衡,促进自闭症谱系障碍 (ASD) 现型.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 自闭症谱系障碍 (ASD) 与神经元超连接性和突触蛋白质合成增加有关.
- 猛素 (mTOR) 途径的哺乳动物点与自闭症有关,但其下游翻译控制机制尚不清楚.
研究的目的:
- 调查真核转化启动因子4E结合蛋白2 (4E-BP2),mTOR的下游抑制剂在调节突触功能和自闭症行为中的作用.
- 阐明神经蛋白的翻译控制机制,与ASD相关的突触后蛋白质.
主要方法:
- 产生了缺乏4E-BP2基因 (Eif4ebp2) 的淘汰赛小鼠.
- 检查了4E-BP2淘汰和真核细胞翻译启动因子4E (eIF4E) 过度表达对神经素翻译的影响.
- 在小鼠中评估了突触刺激与抑制比率和自闭症类行为.
- 利用了eIF4E的药理抑制和神经蛋白水平的正常化.
主要成果:
- 4E-BP2的丧失或eIF4E的过度表达增加了神经质素的翻译.
- Eif4ebp2淘汰赛小鼠表现出高激发性/抑制性突触输入比率和自闭症类行为.
- 对eIF4E的药理抑制或神经素1的正常化恢复了激发-抑制平衡和社会行为.
结论:
- 通过eIF4E及其抑制剂4E-BP2调节的翻译控制对于调节神经蛋白合成至关重要.
- 这种途径的失调会破坏大脑的兴奋抑制平衡,导致类似ASD的表型.
- 针对eIF4E活动或特定的神经蛋白水平可能为ASD提供治疗策略.
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