Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model.
Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model.
复制标题
DOI：
10.1038/ncomms14359
复制
发表时间：
2017-02-20
影响因子：
16.6
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Sethna F;Feng W;Ding Q;Robison AJ;Feng Y;Wang H
脆性X综合征（FXS）是由功能性FMRP缺失引起的，是自闭症的主要原因。缺乏FMRP的神经元显示异常的mRNA翻译和细胞内信号传导。在这里，我们确定，在Fmr 1敲除神经元，1型腺苷酸环化酶（Adcy 1）mRNA的翻译增强，导致ADCY 1蛋白的过度生产和神经元刺激的不敏感性。在Fmr 1基因敲除小鼠中，Adcy 1的遗传减少使异常的ERK 1/2和PI 3 K介导的信号正常化，减弱过度的蛋白质合成并纠正树突棘异常。Adcy 1的遗传减少也改善了自闭症相关的症状，包括重复行为，社交障碍和听源性癫痫发作。此外，外周给药NB 001（一种优先抑制ADCY 1活性而非其他ADCY亚型的实验化合物）可减弱Fmr 1敲除小鼠的行为异常。这些结果表明，在FXS中，Adcy 1翻译升高与ERK 1/2信号传导异常和行为症状之间存在联系。脆性X综合征（FXS）是自闭症的主要原因，缺乏FMRP的神经元显示异常的mRNA翻译和细胞内信号传导。在这里，作者表明，来自Fmr 1敲除小鼠的神经元具有增加的ADCY 1蛋白水平，产生异常的ERK 1/2信号传导，失调的蛋白质合成和与FXS相关的行为症状。
Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice. Genetic reduction of Adcy1 also ameliorates autism-related symptoms including repetitive behaviour, defective social interaction and audiogenic seizures. Moreover, peripheral administration of NB001, an experimental compound that preferentially suppresses ADCY1 activity over other ADCY subtypes, attenuates the behavioural abnormalities in Fmr1 knockout mice. These results demonstrate a connection between the elevated Adcy1 translation and abnormal ERK1/2 signalling and behavioural symptoms in FXS. Fragile X syndrome (FXS) is a leading cause of autism and neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, the authors show that neurons from Fmr1 knockout mice have increased levels of ADCY1 protein, producing abnormal ERK1/2 signalling, dysregulated protein synthesis and behavioural symptoms associated with FXS.