Exploration of the Shared Molecular Mechanisms between COVID-19 and Neurodegenerative Diseases through Bioinformatic Analysis

Abstract

The COVID-19 pandemic has caused millions of deaths and remains a major public health burden worldwide. Previous studies found that a large number of COVID-19 patients and survivors developed neurological symptoms and might be at high risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). We aimed to explore the shared pathways between COVID-19, AD, and PD by using bioinformatic analysis to reveal potential mechanisms, which may explain the neurological symptoms and degeneration of brain that occur in COVID-19 patients, and to provide early intervention. In this study, gene expression datasets of the frontal cortex were employed to detect common differentially expressed genes (DEGs) of COVID-19, AD, and PD. A total of 52 common DEGs were then examined using functional annotation, protein-protein interaction (PPI) construction, candidate drug identification, and regulatory network analysis. We found that the involvement of the synaptic vesicle cycle and down-regulation of synapses were shared by these three diseases, suggesting that synaptic dysfunction might contribute to the onset and progress of neurodegenerative diseases caused by COVID-19. Five hub genes and one key module were obtained from the PPI network. Moreover, 5 drugs and 42 transcription factors (TFs) were also identified on the datasets. In conclusion, the results of our study provide new insights and directions for follow-up studies of the relationship between COVID-19 and neurodegenerative diseases. The hub genes and potential drugs we identified may provide promising treatment strategies to prevent COVID-19 patients from developing these disorders.

Keywords: Alzheimer’s disease; COVID-19; Parkinson’s disease; bioinformatics; differentially expressed genes; drugs; gene ontology; hub genes; protein–protein interaction.

Figure 1

The workflow of this study.

Figure 2

Identification of common DEGs shared by COVID-19, AD, and PD. (A) PCA plots of the COVID-19, AD, and PD expression datasets used in this study after removing batch effects and normalization. (B) Volcano plots of the three datasets. Up-regulated genes are marked in red, and down-regulated genes are marked in blue. (C) Venn diagram (left) reveals that 60 common DEGs are shared among COVID-19, AD, and PD: 9 genes are consistently up-regulated (middle, up arrow) and 43 genes are consistently down-regulated (right, down arrow) in the 3 datasets.

Figure 3

Functional annotation of common DEGs among COVID-19, AD, and PD. (A) GO analysis of shared DEGs and the top 10 terms of each category, including biological process, molecular function, and cellular component, are shown in the dot graph. (B,C) The pathway enrichment analysis results of the KEGG (B) and Reactome (C) databases. The top 10 pathways are exhibited in the bar plots. Count represents the number of DEGs enriched by the term. (D) The GSEA of the three datasets. The enriched common KEGG and GO terms shared by COVID-19, AD, and PD are shown here.

Figure 4

DO enrichment analysis. The chord diagram shows the correlation between diseases and common DEGs, with different colors corresponding to different DO terms.

Figure 5

The PPI network of the identified common DEGs among COVID-19, AD, and PD. The network, including 52 nodes and 320 edges, is generated using String and visualized in Cytoscape. The circle nodes represent the DEGs, and the edges represent the interactions between the nodes; the size and color depth of the nodes are based on the Betweenness Centrality (BC) values.

Figure 6

Detection of hub genes and key module from the PPI network. (A) The critical function module was extracted from the PPI network using the MCODE plugin in Cytoscape. (B,C) The GO annotation (B) and pathway enrichment analysis (C) of the key module. (D) The top 10 genes ranked by MCC, Degree, and BC algorithm. The common five genes, colored in orange, are determined as the hub genes. (E) The verification of the hub genes through the COVID-19, AD, and PD Val_datasets, respectively. *** p < 0.001, ** p < 0.01, * p < 0.05.

Figure 7

The relationship between the candidate drugs and their drug targets.

Figure 8

The network of TF–gene interaction. The blue color nodes represent the common genes, and the rhombus nodes represent the enriched TFs. The network consists of 10 TFs and 42 DEGs in total. The up-regulated DEGs are labeled in red, and the down-regulated DEGs are labeled in blue.