Disease- and headache-specific microRNA signatures and their predicted mRNA targets in peripheral blood mononuclear cells in migraineurs: role of inflammatory signalling and oxidative stress

Abstract

Background Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients. Methods We determined miRNA expression of migraineurs’ PBMC during (ictal) and between (interictal) headaches compared to age- and sex-matched healthy volunteers. Small RNA sequencing was performed from the PBMC, and mRNA targets of miRNAs were predicted using a network theoretical approach by miRNAtarget.com™. Predicted miRNA targets were investigated by Gene Ontology enrichment analysis and validated by comparing network metrics to differentially expressed mRNA data. Results In the interictal PBMC samples 31 miRNAs were differentially expressed (DE) in comparison to healthy controls, including hsa-miR-5189-3p, hsa-miR-96-5p, hsa-miR-3613-5p, hsa-miR-99a-3p, hsa-miR-542-3p. During headache attacks, the top DE miRNAs as compared to the self-control samples in the interictal phase were hsa-miR-3202, hsa-miR-7855-5p, hsa-miR-6770-3p, hsa-miR-1538, and hsa-miR-409-5p. MiRNA-mRNA target prediction and pathway analysis indicated several mRNAs related to immune and inflammatory responses (toll-like receptor and cytokine receptor signalling), neuroinflammation and oxidative stress, also confirmed by mRNA transcriptomics. Conclusions We provide here the first evidence for disease- and headache-specific miRNA signatures in the PBMC of migraineurs, which might help to identify novel targets for both prophylaxis and attack therapy.

A study of differential microRNA expression profile in migraine: the microMIG exploratory study

“…Several authors have made an effort in previous studies to identify potential miRNAs as peripheral biomarkers of migraine [12]. Numerous miRNAs have been described associated with pain-free patients with migraine in comparison to healthy controls: miR-382-5p (overexpressed in serum and PBMC) [21,23]; miR-34a-5p (over-expressed in serum, saliva and PBMC) [21,24]; miR-27b (over-expressed in plasma) [25]; miR-181a, let-7b, and miR-22 (under-expressed in PBMC) [25]; miR-155, miR-126, and let-7 g (over-expressed in plasma) [18]; miR-30 (over-expressed in PBMC) [69]; miR-5189-3p, miR-3613-5p, miR-99a-3p, miR-542-3p (over-expressed in PBMC) and miR-96-5p (under-expressed) [26]. Results are heterogenous and study-dependent but not only because there are differences in lab procedures, biological matrix or sample size but mainly because of the large degree of heterogeneity between study groups.…”

“…Several pilot studies have described miRNAs as potential peripheral biomarkers of migraine disease [18][19][20][21][22][23][24][25][26]. Nevertheless, studies are scarcely comparable and reproducible not only because of the lack of standardized protocols, biological matrix or sample size but mainly because of the heterogeneous population and clinical variability included.…”

The holistic approach to the CHRNA7 gene, hsa-miR-3158-5p, and 15q13.3 hotspot CNVs in migraineurs

“…Among the molecules currently under investigation, miRNAs have significant potential. 45 Migraine-specific miRNAs have been discovered in miRNA analyzes of peripheral blood monocytes of migraine patients. In our study, miR-3158-5p has potential as one of the migraine diagnosis candidates.…”

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure 1A). 83−85 Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, 4−6 oxidative stress, 7 cell proliferation, 8,9 inflammation, 10,11 hematopoiesis, 4,12 and tumorigenesis. 13,14 Recent studies revealed that miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine.…”

“…A particular miRNA can target various mRNAs to induce translational repression or RNA degradation, and one mRNA can be regulated by multiple different miRNAs . By modulating gene expression at the post-translational level, miRNAs play a critical role in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , Importantly, miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine. − Therefore, circulating miRNAs are considered biomarkers of disease and can regulate gene expression in distal cells or organs. ,, …”