Autism-related deficits via dysregulated eIF4E-dependent translational control.
Autism-related deficits via dysregulated eIF4E-dependent translational control.
复制标题
作者：
由于突触蛋白合成增加而导致的神经元回路的超连通性被认为是导致自闭症谱系障碍（ASD）的原因。哺乳动物雷帕霉素靶蛋白（mTOR）通过上游信号传导与ASD密切相关。然而，下游监管机制不明确。我们表明，真核翻译起始因子4 E结合蛋白2（4 E-BP 2），mTOR下游的eIF 4 E-阻遏物，或eIF 4 E过表达的敲除（KO）导致神经连接素的翻译增加，神经连接素是与ASD因果相关的突触后蛋白。4 E-BP 2-KO小鼠表现出兴奋性与抑制性突触输入的比率增加和自闭症样行为：社交互动缺陷、交流改变和重复/刻板行为。eIF 4 E活性的药理学抑制或神经连接蛋白1（但不是神经连接蛋白2）蛋白量的正常化，恢复正常的兴奋/抑制比并纠正社会行为缺陷。因此，通过eIF 4 E的翻译控制调节神经连接素的合成，维持兴奋与抑制的平衡，并且其失调产生ASD样表型。
Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is postulated to cause Autism Spectrum Disorders (ASD). The mammalian target of rapamycin (mTOR) is strongly implicated in ASD via upstream signaling. However, downstream regulatory mechanisms are ill-defined. We show that knockout (KO) of the eukaryotic translation Initiation Factor 4E-Binding Protein 2 (4E-BP2), an eIF4E-repressor downstream of mTOR, or eIF4E overexpression lead to increased translation of neuroligins, which are post-synaptic proteins that are causally linked to ASD. 4E-BP2-KO mice exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors: social interaction deficits, altered communication and repetitive/stereotyped behaviors. Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2 protein amounts, restore the normal excitation/inhibition ratio and rectify the social behavior deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation to inhibition balance, and its dysregulation engenders ASD-like phenotypes.
登录
查看更多内容
影响因子：
3.9
作者：
Cornew, Lauren;Roberts, Timothy P. L.;Blaskey, Lisa;Edgar, J. Christopher
通讯作者：
Edgar, J. Christopher
影响因子：
16
作者：
Bidinosti M;Ran I;Sanchez-Carbente MR;Martineau Y;Gingras AC;Gkogkas C;Raught B;Bramham CR;Sossin WS;Costa-Mattioli M;DesGroseillers L;Lacaille JC;Sonenberg N
通讯作者：
Sonenberg N
影响因子：
5.3
作者：
Banko, JL;Poulin, F;Klann, E
通讯作者：
Klann, E
DOI：
10.1097/01.dbp.0000267563.18952.c9
发表时间：
2007-04-01
影响因子：
2.4
作者：
Nowicki, Stephen T.;Tassone, Flora;Hagerman, Randi J.
通讯作者：
Hagerman, Randi J.
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric