阿尔茨海默病患者皮层金属离子转运基因的生物信息学特征

Bioinformatics characterization of metal ion transport genes in the cortex of patients with Alzheimer's disease

目的研究阿尔茨海默病(AD)患者皮层差异性金属离子转运基因的分子功能、生物学过程分类、分子调控网络的变化特征及关键节点,为AD的早期临床诊断和防治提供新方法和新思路。方法从基因芯片公共数据库(GEO)中下载AD患者皮层基因芯片数据,筛选与金属离子转运相关的差异基因,采用PANTHER在线平台对差异基因进行基因本体(GO)分析,包括基因分类、分子功能、生物学过程及信号通路分析,应用STRING11.0在线分析软件对差异基因进行生物信息学调控网络分析,寻找关键节点基因,并使用Metascape在线软件分析基因功能簇间的相互作用关系,并筛选重要的基因功能簇。结果在AD患者皮层基因中筛选出30个与金属离子转运相关的差异基因,均表达上调,其生物学功能主要与跨膜信号转导、金属离子跨膜转运、细胞内金属离子稳态、基因特异性转录调节、蛋白质结合活性调节相关,与离子型谷氨酸受体信号通路、α肾上腺素能受体信号通路密切相关。蛋白-蛋白相互作用(PPI)调控网络中的子网络分别与调节金属蛋白酶水解、调节电压依赖性钙通道及介导跨膜蛋白进入线粒体内膜密切相关,关键节点包括电压依赖性钙离子通道亚基α2/δ1(CACNA2D1)、N-甲基-D-天冬氨酸离子能谷氨酸受体(GRIN)1、GRIN3A、电压门控钾离子通道亚家族D(KCND)3、电压门控钾离子通道亚家族Q(KCNQ)1及KCNQ5。结论AD的发病机制与皮层组织中的CACNA2D1、GRIN1、GRIN3A、KCND3、KCNQ1及KCNQ5等基因的变化密切相关,主要涉及离子型谷氨酸受体信号通路及α肾上腺素能受体信号通路。

Objective To study the molecular function,biological process category,molecular regulation network feature and key nodes of differently expressed metal ion transporter genes from cortex of Alzheimer's disease(AD)patients to provide new method and thought for clinical treatment of AD at early stage.Methods The microarray genes data from cortex of AD patients were downloaded from the gene expression omnibus database(GEO)to screen for differential genes associated with metal ion transport.The PANTHER online platform was used for gene ontology(GO)analysis of differential genes,including gene classification,molecular function,biological process and signaling pathway analysis.The STRING11.0 online analysis software was used to analyze the bioinformatics regulatory network of differential genes,and the key node genes were found.The Metascape online software was used to analyze the interaction between gene functional clusters and screen important gene functional clusters.Results 30 differential genes related to metal ion transport were screened from the cortical genes of AD patients,all of which were up-regulated.Their biological functions were mainly related to transmembrane signal transduction,metal ion transmembrane transport,intracellular metal ion homeostasis,gene specific transcriptional regulation,protein-binding activity regulation and they were closely related to ionotropic glutamate receptor signaling pathway andαadrenergic receptor signaling pathway.The sub-networks in protein-protein interaction(PPI)regulatory network were strongly linked to the regulation of metalloproteinase hydrolysis,regulation of voltage-dependent calcium channel and mediating transmembrane proteins inner mitochondrial membrane.Alpha2 delta1 subunit of voltage-gated calcium channel(CACNA2D1),recombinant glutamate receptor,ionotropic,N-methyl-D-aspartate(GRIN)1,GRIN3A,potassium voltage-gated channel subfamily D(KCND)3,potassium voltage-gated channel subfamily Q(KCNQ)1 and KCNQ5 were key nodes of sub-networks.Conclusions The pathogenesis of AD is closely related to the changes of CACNA2D1,GRIN1,GRIN3A,KCND3,KCNQ1 and KCNQ5 genes in cortical tissue,mainly involving the ionotropic glutamate receptor signaling pathway andαadrenergic receptor signaling pathway.