Exploring the Regulatory Role of miRNA in Connecting Parkinson's Disease with Pesticide Exposure in an Egyptian Cohort

Abstract Micro-RNAs, a class of small non-coding RNA molecules, play a significant role in the intricate complex mechanisms underlying the pathophysiology of Parkinson’s disease (PD). PD is a common neurodegenerative condition that leads to significant morbidity and a decline in quality of life. Nevertheless, the development of PD is influenced by environmental factors, and the complex nature of these relationships is further complicated by a multitude of factors, including genetic backgrounds specific to populations and variations in environmental exposures, such as pesticides. Therefore, the aim of this study was to compare the expression profiles of a set of candidate miRNAs that are associated with the pathogenesis of PD and pesticide exposure. The study focused on examining the expression of hsa-miR34c-5p, hsa -miR132-3p, hsa -miR-7-5p, hsa- miR-181a-5p, hsa -miR-29c,3then mild then mild-5p, and hsa-miR-17-5p in peripheral blood mononuclear cells (PBMCs) derived from Egyptian patients with PD and comparing them to a control group and then mild and severe stages of PD patients, along with the reference controls, to ascertain whether there is a correlation between the expression of these miRNAs and the severity of the disease. Additionally, we explored the role of these miRNAs in the early events of PD by comparing the expression profiles of patients with early-onset and normal-onset PD with those of the reference group. The levels of miRNA expression in PBMCs obtained from 52 patients with PD and 39 control subjects were evaluated using reverse transcription-quantitative real-time PCR. We also assessed the ability of these expression levels to distinguish between patients with PD and reference individuals by ROC curve analysis. We also applied a consensus, integrated approach to construct a dysregulated miRNA-based network to identify the respective targets and transcription factors. In addition, enrichment analysis was performed to obtain enriched gene ontology and pathways. Significant downregulation of hsa-miR-34c-5p, miR-132-3p, miR-7-5p, and miR-29c-3p was observed. Meanwhile, miR-181a-5p were significantly upregulated. In contrast, miR-155-5p and miR-17-5p did not show any significant differences in expression levels between the two studied groups. Nevertheless, the level of expression of miR-17 showed a significant upregulation correlated with disease severity. The expression levels of miR-34c, miR-132, miR-7, and miR-17 showed downregulation in the mild stage of PD compared with the reference group and were higher in the severe stages of the disease compared with the mild stages of PD. Additionally, a significant upregulation of miR-181a was observed in the early onset of PD patients compared with the reference group. miR-132, miR7, and miR-29c showed noteworthy downregulation in the early onset compared with the control group. miR-7 and miR-29c showed a good value of AUC = (0.764, 0.795) to discriminate between individuals with PD and the reference control group; moreover, miR-132 reported a significant AUC = 0.816 to differentiate between mild PD patients and the control group, which considered its ability to be a blood biomarker. In addition, the seven miRNAs were linked to known PD pathways, and the candidate-related target genes were presented in the visualized Cytoscape network. The in-silico analysis also identified candidate target genes and TFs, including those related to neurodegeneration and PD. Our computational analysis has successfully identified potential target genes and transcription factors, specifically those associated with neurodegeneration and Parkinson’s disease (PD). Overall, our results could contribute toward a better understanding of the possible regulatory mechanisms governing the role of pesticides in PD development, thereby providing a compelling basis for deeper identification of the specific functions of the detected miRNAs in PD and their possible role in pesticide exposure.