Effects of DISC1 on Alzheimer's disease cell models assessed by iTRAQ proteomics analysis.

Jiajie Lu,Zhaotao Wang,Yongyang Fan,Rihong Huang,Yuecheng Peng,Zejia Feng,Zhaorong Zeng,Yezhong Wang,Haojian Wang,Jiana Wei

doi:10.1042/bsr20211150

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease, and accounts for almost 80% of the dementia cases worldwide [1]
We found Disrupted in Schizophrenia 1 (DISC1) is up-regulated in HEK-amyloid precursor protein (APP) cells compared with the control group (Supplementary Figure S1)
A total of 351 differentially expressed protein (DEP) (Supplementary Table S1) were identified in the DISC1high AD cells relative to the control cells, and the top 20 up-regulated and down-regulated proteins are listed in Tables 1 and 2, respectively

Summary

Introduction

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease, and accounts for almost 80% of the dementia cases worldwide [1] It commonly afflicts the elderly (>65 years), known as the late-onset AD, and early-onset AD that affects those younger than 65 years of age is relatively rare [2]. Disrupted in Schizophrenia 1 (DISC1) is a multifunctional scaffold protein that is ubiquitous in the brain, and highly expressed in the temporal and para-hippocampal cortices, dentate gyrus of the hippocampus, and the white matter [6] It interacts with multiple proteins involved in physiological processes such as neuron migration, neural progenitor cell (NPC) proliferation, neural signal transmission and synaptic functions, indicating a pathological role in neurodegeneration as well as a potential target for drug intervention [7]. We ectopically expressed DISC1 in the amyloid precursor protein (APP) cellular model of AD, and compared the proteomes of the control and overexpressing cells to identify the differentially expressed proteins (DEPs)

Methods

Results

Conclusion