Integrative analysis of plasma and substantia nigra in Parkinson's disease: unraveling biomarkers and insights from the lncRNA-miRNA-mRNA ceRNA network

Abstract

Introduction: Parkinson's disease (PD) is a rapidly growing neurological disorder characterized by diverse movement symptoms. However, the underlying causes have not been clearly identified, and accurate diagnosis is challenging. This study aimed to identify potential biomarkers suitable for PD diagnosis and present an integrative perspective on the disease.

Methods: We screened the GSE7621, GSE8397-GPL96, GSE8397-GPL97, GSE20163, and GSE20164 datasets in the NCBI GEO database to identify differentially expressed (DE) mRNAs in the substantia nigra (SN). We also screened the GSE160299 dataset from the NCBI GEO database to identify DE lncRNAs and miRNAs in plasma. We then constructed 2 lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) regulatory networks based on the ceRNA hypothesis. To understand the biological function, we performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses for each ceRNA network. The receiver operating characteristic analyses (ROC) was used to assess ceRNA results.

Results: We identified 7 upregulated and 29 downregulated mRNAs as common DE mRNAs in the 5 SN datasets. In the blood dataset, we identified 31 DE miRNAs (9 upregulated and 22 downregulated) and 332 DE lncRNAs (69 upregulated and 263 downregulated). Based on the determined interactions, 5 genes (P2RX7, HSPA1, SLCO4A1, RAD52, and SIRT4) appeared to be upregulated as a result of 10 lncRNAs sponging 4 miRNAs (miR-411, miR-1193, miR-301b, and miR-514a-2/3). Competing with 9 genes (ANK1, CBLN1, RGS4, SLC6A3, SYNGR3, VSNL1, DDC, KCNJ6, and SV2C) for miR-671, a total of 26 lncRNAs seemed to function as ceRNAs, influencing genes to be downregulated.

Discussion: In this study, we successfully constructed 2 novel ceRNA regulatory networks in patients with PD, including 36 lncRNAs, 5 miRNAs, and 14 mRNAs. Our results suggest that these plasma lncRNAs are involved in the pathogenesis of PD by sponging miRNAs and regulating gene expression in the SN of the brain. We propose that the upregulated and downregulated lncRNA-mediated ceRNA networks represent mechanisms of neuroinflammation and dopamine neurotransmission, respectively. Our ceRNA network, which was associated with PD, suggests the potential use of DE miRNAs and lncRNAs as body fluid diagnostic biomarkers. These findings provide an integrated view of the mechanisms underlying gene regulation and interactions in PD.

Keywords: GEO database; Parkinson’s disease; bioinformatics analysis; biomarker; ceRNA network; lncRNA; meta-analysis; microRNA.

Figure 1

Flow chart of our study. Data collection, processing, construction of ceRNA network, and KEGG & GO analysis. GEO, gene expression omnibus; PD, Parkinson’s disease; DE, differential expression; FC, fold change; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Figure 2

Venn diagrams, heatmap plots, and volcano plots of differentially expressed mRNAs, miRNAs, and lncRNAs. (A) Venn diagram and heatmap plot of upregulated mRNAs. Genes belong to the red area of the Venn diagram used for heatmap analysis. (B) Venn diagram and heatmap plot of downregulated mRNAs. Genes belong to the blue area of the Venn diagram used for heatmap analysis. (C) Volcano plot of differentially expressed miRNAs and lncRNAs. Red indicates upregulated and blue indicates downregulated.

Figure 3

Construction of lncRNA–miRNA–mRNA ceRNA regulatory network. (A) The lncRNA-mediated upregulated ceRNA network. (B) The lncRNA-mediated downregulated ceRNA network. Red, green, and blue indicate lncRNA, miRNA, and mRNA, respectively.

Figure 4

The bubble plots of KEGG pathway analysis results. (A) Results for the upregulated ceRNA network. (B) Results for the downregulated ceRNA network. The color and size of bubbles indicate the number of genes associated with each pathway and the -log 10 (FDR), respectively.

Figure 5

The receiver operating characteristic (ROC) curve analysis results for each ceRNA network. (A) ROC curve of DE miRNAs and DE lncRNAs on upregulated ceRNA network. (B) ROC curve of DE miRNAs and DE lncRNAs on downregulated ceRNA network.