Downregulation of ATP6V1A Involved in Alzheimer's Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation.

Zhike Zhou,Kexin Kang,Mei Zhao,Shanshan Zhong,Ying Xu,Rongwei Zhang,Xiaoqian Zhang,Chuansheng Zhao,Jun Bai,Daniele Vergara

doi:10.1155/2021/5555634

Abstract

Objective The objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer's disease (AD). Methods Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. Results The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. Conclusions Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Highlights

Alzheimer’s disease (AD), referring to a progressive neurodegenerative disease, is pathologically characterized by extracellular senile plaques composed of amyloid beta (Aβ), neurofibrillary tangles composed of hyperphosphorylated tau, and neuron loss [1, 2]
The mean expression of ATP6V1A in the temporal cortex of AD (8:04 ± 0:41) was significantly lower than that of nondementia controls (8:42 ± 0:46; P = 0:001) (Figure 2(a)). This was consistent with western blot (Supplementary Figures 1A and 1B) and qRT-PCR (Supplementary Figure 1C) analyses of ATP6V1A expression between Mount Sinai Brain Bank (MSBB) Brodmann area 36 parahippocampal gyrus (BM36PHG) samples of AD and normal controls [31]
The results emerging from weight gene correlation network analysis (WGCNA) revealed that the blue, brown, and turquoise modules were significantly correlated with AD and ATP6V1A, which were involved in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and GABAergic synapse

Summary

Introduction

Alzheimer’s disease (AD), referring to a progressive neurodegenerative disease, is pathologically characterized by extracellular senile plaques composed of amyloid beta (Aβ), neurofibrillary tangles composed of hyperphosphorylated tau, and neuron loss [1, 2]. As the major processing compartment for Aβ, lysosomes rely on an acidic environment of pH less than 5.0 to activate proteases for Aβ degradation [4, 5]. This gradient of acidification is potentially mediated by vacuolar H+-ATPase (V-ATPase), a multisubunit enzyme consisting of V0 and V1 sectors that pumps protons into the lysosomal lumen by ATP consumption [6]. ATP6V1A assembles with V0 subunits to form the glucose-dependent complex of V1/Vo sectors that drives proton transport; simultaneously, this process can be interrupted by reversible dissociation of the complex into component V0 and V1 [10]. We sought to perform a comprehensive bioinformatics analysis of ATP6V1A based on gene expression data and functional annotations, aiming to elucidate the molecular functions of ATP6V1A underlying the pathogenesis of AD

Methods

Results

Conclusion