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Autism-related deficits via dysregulated eIF4E-dependent translational control

机译：通过失调的eIF4E依赖性翻译控制引起的自闭症相关缺陷

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摘要

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.%异常蛋白合成曾被假设是造成“自闭症症候群”(ASDs)的一个机制，但关于哪些通道被破坏的详细情况仍不清楚。elF4E(翻译启动的一个关键因子)的破坏曾被发现与人类自闭症有关，而现在，两篇独立的论文又发现，过度的cap-dependerlt翻译与小鼠的突触及ASD-相关的行为缺陷有关。Nahum Sonenberg及其同事发现，缺失4E-BP2(一个elF4阻遏因子)的小鼠表现出“神经连接蛋白”(与自闭症有很大关系的突触蛋白)的翻译增加。这些小鼠还表现出与ASD相关的行为和海马体突触活动的改变，它们会被elF4E活动或“神经连接蛋白-1”水平的正常化逆转。Eric Klann及其同事发现，过度表达elF4E的小鼠还表现出与ASD相关的行为和海马体中、前额皮质中和纹状体中突触活动的改变，而且一些表现型还可通过cap-dependerlt翻译的抑制因子4EGI-1被挽救。这两项研究的共同结果表明，cap-dependent翻译是治疗与ASD相关症状的一个潜在治疗目标。
机译：人们认为，由于突触蛋白合成增加导致神经元回路的超连通性会导致自闭症谱系障碍（ASD）。雷帕霉素（mTOR）的哺乳动物靶标通过上游信号强烈参与ASD。但是，下游的监管机制尚不明确。在这里，我们显示真核翻译起始因子4E结合蛋白2（4E-BP2）-mTOR-或eIF4E过表达下游的eIF4E阻遏物的敲除导致神经胶蛋白的翻译增加，神经胶蛋白是因果关系到ASD的突触后蛋白。敲除编码4E-BP2（Eif4ebp2）的基因的小鼠表现出兴奋性与抑制性突触输入和自闭症样行为（即，社交互动障碍，交流改变和重复/刻板行为）比例增加。对eIF4E活性的药理抑制或神经胶蛋白1的正常化，而非神经胶蛋白2的正常化，蛋白质水平恢复了正常的兴奋/抑制比并纠正了社会行为缺陷。因此，eIF4E的翻译控制调节神经胶蛋白的合成，维持兴奋-抑制平衡，并且其失调引起ASD样表型。％异常蛋白合成曾被假设是造成“自闭症症候群”（ASDs）的一个。 elF4E（翻译启动的一个关键因素）的破坏曾被发现与人类自闭症有关，而现在，两篇独立的论文又发现，过度的上限-ahman Sonenberg及其同事发现，缺失4E-BP2（一个elF4阻遏因子）的小鼠表现出“神经连接蛋白”（与自闭症）。这些小鼠还表现出与ASD相关的行为和海马体突触活动的改变，它们会被elF4E活动或“神经连接蛋白-1”水平的正常化。逆转。EricKlann及其同事发现，过度表达elF4E的小鼠还表现出与ASD相关的行为和海马体中，前额皮质中和纹状体中突触活动的改变，而且一些表现型或通过盖帽-依赖性翻译的抑制因子4EGI-1被挽救。这是研究的共同结果表明，盖帽依赖性的翻译是治疗与ASD相关症状的一个潜在治疗目标。

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  • 来源
    《Nature》 |2013年第7432期|371-377qt3|共8页
  • 作者

    Christos G. Gkogkas; Arkady Khoutorsky; Israeli Ran; Emmanouil Rampakakis; Tatiana Nevarko; Daniel B. Weatherill; Cristina Vasuta; Stephanie Yee; Morgan Truitt; Paul Dallaire; Francois Major; Paul Lasko; Davide Ruggero; Karim Nader; Jean-Claude Lacaille; Nahum Sonenberg;

  • 作者单位

    Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada;

    Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada;

    GRSNC and Department of Physiology, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada,JSS Medical Research Inc., Montreal, Quebec H4S 1N8, Canada;

    Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada;

    GRSNC and Department of Physiology, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    GRSNC and Department of Physiology, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Department of Biology, McGill University, Montreal, Quebec H3G OBI, Canada;

    School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA;

    Institute for Research in Immunology and Cancer, and Department of Computer Science, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Institute for Research in Immunology and Cancer, and Department of Computer Science, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Department of Biology, McGill University, Montreal, Quebec H3G OBI, Canada;

    School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA;

    Department of Psychology, McGill University, Montreal, Quebec H3A 1B1, Canada;

    GRSNC and Department of Physiology, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada;

    Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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