nature20130117-1

来自麦基尔大学和蒙特利尔大学的研究者确定了自闭症谱系障碍(ASD)与蛋白质合成途径之间的关键联系,为开发新的医疗手段提供了支持。

-2013年1月17日《自然》

中文翻译


【题目】 eIF4E依赖的转录控制失调引起自闭症相关缺陷

【译文】因突触蛋白合成增加而引起的神经回路超连接被认为会造成自闭症(ASD)。哺乳动物中的雷帕霉素靶点(mTOR)通过上游信号途径与ASD显著相关;然而,下游调控机制尚不清楚。本研究表明敲除真核生物翻译抑制因子4E结合蛋白2(4E-BP2,mTOR下游的一种eIF4E抑制因子)或eIF4E过表达会导致神经连接蛋白翻译增加,神经连接蛋白是与ASD相关的突触后蛋白。敲除编码4E-BP2 (Eif4ebp2)基因的小鼠其兴奋性和抑制性突触输入的比例增加,并且其自闭症样行为(即社交缺陷、交流变化和重复/刻板行为)也有所增加。当药理学抑制eIF4E活性或神经连接蛋白1时,蛋白水平正常化会使得兴奋性/抑制性比例恢复正常,并修正社交行为缺陷,而抑制神经连接蛋白2则不会产生这样的效果。因此,依赖eIF4E的翻译控制调控了神经连接蛋白的合成,维持了兴奋与抑制的平衡,而这种平衡的失调会引起ASD样表型。

英文原稿


[Title]: Autism-related deficits via dysregulated eIF4E-dependent translational control

[Authors]:Christos G. Gkogkas,1 Arkady Khoutorsky,1, 8 Israeli Ran,2, 8 Emmanouil Rampakakis,1, 3 Tatiana Nevarko,1 Daniel B. Weatherill,2 Cristina Vasuta,2 Stephanie Yee,4 Morgan Truitt,5 Paul Dallaire,6 François Major,6 Paul Lasko,4 Davide Ruggero,5 Karim Nader,7 Jean-Claude Lacaille2 & Nahum Sonenberg1

[Abstract]Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)—an eIF4E repressor downstream of mTOR—or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.

原文地址

http://www.nature.com/nature/journal/v493/n7432/full/nature11628.html

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