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. 2021 Jun 6;10(6):1410.
doi: 10.3390/cells10061410.

Regulatory miRNA-mRNA Networks in Parkinson's Disease

Bruno Lopes Santos-Lobato  1   2 , Amanda Ferreira Vidal  2   3   4 , Ândrea Ribeiro-Dos-Santos  2   4
Affiliations

Regulatory miRNA-mRNA Networks in Parkinson's Disease

Bruno Lopes Santos-Lobato et al. Cells. .

Abstract

Parkinson's disease (PD) is the second-most common neurodegenerative disease, and its pathophysiology is associated with alpha-synuclein accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. MicroRNAs are small non-coding RNAs that regulate gene expression, and many previous studies have described their dysregulation in plasma, CSF, and in the brain of patients with PD. In this study, we aimed to provide a regulatory network analysis on differentially expressed miRNAs in the brain of patients with PD. Based on our systematic review with a focus on the substantia nigra and the putamen, we found 99 differentially expressed miRNAs in brain samples from patients with PD, which regulate 135 target genes. Five genes associated with neuronal survival (BCL2, CCND1, FOXO3, MYC, and SIRT1) were modulated by dysregulated miRNAs found in the substantia nigra and the putamen of patients with PD. The functional enrichment analysis found FoxO and PI3K-AKT signaling as pathways related to PD. In conclusion, our comprehensive analysis of brain-related miRNA-mRNA regulatory networks in PD showed that mechanisms involving neuronal survival signaling, such as cell cycle control and regulation of autophagy/apoptosis, may be crucial for the neurodegeneration of PD, being a promising way for novel disease-modifying therapies.

Keywords: Parkinson’s disease; differentially expressed; microRNA; neuronal survival signaling.

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Conflict of interest statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1
Figure 1
Number of shared target genes between the four sets of differentially expressed miRNAs (vertical bars). The lower part of the figure shows the intersection of sets associated with the vertical bars (dots connected by black lines).
Figure 2
Figure 2
Enriched KEGG pathways for the target genes regulated by the four sets of differentially expressed miRNAs. (A) Upregulated DE-miRNAs’ target gene enrichment. (B) Downregulated DE-miRNAs’ target gene enrichment. (C) Substantia nigra DE-miRNAs’ target gene enrichment. (D) Putamen DE-miRNAs’ target genes enrichment. The color of the circles indicates the significance of the pathway, and the size of the circles indicates the number of target genes involved in each pathway.
Figure 3
Figure 3
Regulatory networks for the four sets of differentially expressed miRNAs including the top 20 hub nodes. (A) Upregulated DE-miRNAs–mRNA network. (B) Downregulated DE-miRNAs–mRNA network. (C) Substantia nigra DE-miRNAs–mRNA network. (D) Putamen DE-miRNAs–mRNA network. The node size indicates degree centrality, and the scale of the node color indicates betweenness centrality. The center of the network displays the top five hub nodes according to degree centrality.
Figure 4
Figure 4
Heatmaps showing the hierarchical clustering of the global expression of the target genes regulated by the four sets of differentially expressed miRNAs across human brain tissues from the Genotype-Tissue Expression. (A) Upregulated DE-miRNAs’ hub genes expression. (B) Downregulated DE-miRNAs’ hub genes expression. (C) Substantia nigra DE-miRNAs’ hub gene expression. (D) Putamen DE-miRNAs’ hub gene expression.
See this image and copyright information in PMC

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