Institute of Neuroscience, Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Institute of Neuroscience, Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Biosci Rep. 2022 Jan 28;42(1). doi: 10.1042/BSR20211150.
Alzheimer's disease (AD) is a form of neurodegenerative disease in the elderly with no cure at present. In a previous study, we found that the scaffold protein, disrupted in Schizophrenia 1 (DISC1) is down-regulated in the AD brains, and ectopic expression of DISC1 can delay the progression of AD by protecting synaptic plasticity and down-regulating BACE1. However, the underlying mechanisms remain not to be elucidated. In the present study, we compared the proteomes of normal and DISC1high AD cells expressing the amyloid precursor protein (APP) using isobaric tag for relative and absolute quantitation (iTRAQ) and mass spectrometry (MS). The differentially expressed proteins (DEPs) were identified, and the protein-protein interaction (PPI) network was constructed to identify the interacting partners of DISC1. Based on the interaction scores, NDE1, GRM3, PTGER3 and KATNA1 were identified as functionally or physically related to DISC1, and may therefore regulate AD development. The DEPs were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases with the DAVID software, and the Non-supervised Orthologous Groups (eggNOG) database was used to determine their evolutionary relationships. The DEPs were significantly enriched in microtubules and mitochondria-related pathways. Gene set enrichment analysis (GSEA) was performed to identify genes and pathways that are activated when DISC1 is overexpressed. Our findings provide novel insights into the regulatory mechanisms underlying DISC1 function in AD.
阿尔茨海默病（AD）是一种老年人神经退行性疾病，目前尚无治愈方法。在之前的一项研究中，我们发现支架蛋白精神分裂症 1 （DISC1）在 AD 脑中表达下调，DISC1 的异位表达可以通过保护突触可塑性和下调 BACE1 来延缓 AD 的进展。然而，其潜在机制仍不清楚。在本研究中，我们使用相对和绝对定量同位素标记（iTRAQ）和质谱（MS）比较了表达淀粉样前体蛋白（APP）的正常和 DISC1high AD 细胞的蛋白质组。鉴定差异表达蛋白（DEPs），并构建蛋白质-蛋白质相互作用（PPI）网络以鉴定 DISC1 的相互作用伙伴。基于相互作用得分，确定 NDE1、GRM3、PTGER3 和 KATNA1 与 DISC1 具有功能或物理相关性，因此可能调节 AD 的发展。使用 DAVID 软件对 DEPs 进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）数据库的功能注释，使用非监督同源群（eggNOG）数据库确定其进化关系。DEPs 在微管和线粒体相关途径中显著富集。进行基因集富集分析（GSEA）以鉴定当 DISC1 过表达时激活的基因和途径。我们的研究结果为 DISC1 在 AD 中的功能调节机制提供了新的见解。
