Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.
Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.
复制标题
DOI：
10.1016/j.cels.2015.11.002
复制
发表时间：
2015-11-25
期刊：
影响因子：
9.3
通讯作者：
Snyder M
中科院分区：
文献类型：
--
作者：
Li J;Ma Z;Shi M;Malty RH;Aoki H;Minic Z;Phanse S;Jin K;Wall DP;Zhang Z;Urban AE;Hallmayer J;Babu M;Snyder M
自闭症谱系障碍（ASD）的患病率正在迅速增长，但其分子基础却知之甚少。我们使用了一个系统的方法，其中ASD候选基因被映射到无处不在的人类蛋白质复合物和所产生的复合物的特点。这些研究揭示了组蛋白去乙酰化酶（HDAC 1/2）在调节胚胎小鼠脑中ASD直系同源物表达中的作用。在神经元细胞中对HDAC 1和其他六种关键ASD蛋白的共复合亚基的蛋白质组范围的筛选揭示了蛋白质相互作用网络，其在胎儿脑发育中显示优先表达，在ASD病例中表现出增加的有害突变，并且分别受到脆性X和Rett综合征的FMRP和MECP 2的强烈调控。总的来说，我们的研究揭示了ASD的分子组成，表明ASD的综合征和特发性形式之间存在共同的机制，并为分析复杂的人类疾病提供了系统框架。
The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.