Integrating the Alzheimer's Disease Proteome and Transcriptome: A Comprehensive Network Model of a Complex Disease
Integrating the Alzheimer's Disease Proteome and Transcriptome: A Comprehensive Network Model of a Complex Disease
复制标题
DOI：
10.1089/omi.2011.0054
复制
发表时间：
2012-02-01
影响因子：
3.3
通讯作者：
Thomas, Michael A.
中科院分区：
文献类型：
--
作者：
Hallock, Peter;Thomas, Michael A.
网络模型与基因表达研究相结合，已经成为研究阿尔茨海默病等复杂疾病的有用工具。我们通过对原始文献的整理，构建了一个“核心”阿尔茨海默病蛋白相互作用网络。核心网络由775个节点和2,204个交互组成。据我们所知，这是迄今为止为阿尔茨海默病构建的最全面、最准确的蛋白质相互作用网络。通过添加额外的与核心网络蛋白相互作用的蛋白质，通过计算构建了一个由4,945个节点和26,064个相互作用组成的“扩展”网络。然后，我们将现有的基因表达研究映射到核心网络。这个联合数据模型确定MAPK/ERK通路和笼蛋白介导的受体内吞作用是阿尔茨海默病的关键通路。在核心网络中相互作用的MAPK/ERK通路中的重要蛋白形成了下调的节点簇，而在核心网络中相互作用的网状蛋白和几个网状蛋白辅助蛋白形成了上调的节点簇。MAPK/ERK通路是突触可塑性和学习过程中的关键组成部分，阿尔茨海默病的突触可塑性和学习过程被破坏。网状蛋白和网状蛋白适配器蛋白参与APP蛋白的内吞作用，可导致细胞内淀粉样β多肽水平增加，从而促进阿尔茨海默病的进展。
Network models combined with gene expression studies have become useful tools for studying complex diseases like Alzheimer's disease. We constructed a "Core" Alzheimer's disease protein interaction network by human curation of the primary literature. The Core network consisted of 775 nodes and 2,204 interactions. To our knowledge, this is the most comprehensive and accurate protein interaction network yet constructed for Alzheimer's disease. An "Expanded" network was computationally constructed by adding additional proteins that interacted with Core network proteins, and consisted of 4,945 nodes and 26,064 interactions. We then mapped existing gene expression studies to the Core network. This combined data model identified the MAPK/ERK pathway and clathrin-mediated receptor endocytosis as key pathways in Alzheimer's disease. Important proteins in the MAPK/ERK pathway that interacted in the Core network formed a downregulated cluster of nodes, whereas clathrin and several clathrin accessory proteins that interacted in the Core network formed an upregulated cluster of nodes. The MAPK/ERK pathway is a key component in synaptic plasticity and learning, processes disrupted in Alzheimer's. Clathrin and clathrin adaptor proteins are involved in the endocytosis of the APP protein that can lead to increased intracellular levels of amyloid beta peptide, contributing to the progression of Alzheimer's.