Clinical Insights into MicroRNAs in Depression: Bridging Molecular Discoveries and Therapeutic Potential

Abstract

Depression is a major contributor to the overall global burden of disease. The discovery of biomarkers for diagnosis or prediction of treatment responses and as therapeutic agents is a current priority. Previous studies have demonstrated the importance of short RNA molecules in the etiology of depression. The most extensively researched of these are microRNAs, a major component of cellular gene regulation and function. MicroRNAs function in a temporal and tissue-specific manner to regulate and modify the post-transcriptional expression of target mRNAs. They can also be shuttled as cargo of extracellular vesicles between the brain and the blood, thus informing about relevant mechanisms in the CNS through the periphery. In fact, studies have already shown that microRNAs identified peripherally are dysregulated in the pathological phenotypes seen in depression. Our article aims to review the existing evidence on microRNA dysregulation in depression and to summarize and evaluate the growing body of evidence for the use of microRNAs as a target for diagnostics and RNA-based therapies.

Keywords: antidepressant; biomarker; depression; extracellular vesicles; major depressive disorder; miRNA therapeutics; microRNA.

Figure 1

Biogenesis and mechanisms of miRNA-mediated gene regulation. This figure illustrates the miRNA gene expression pathway and subsequent miRNA-mediated gene silencing mechanisms. The process begins in the nucleus, where the miRNA gene is transcribed by RNA polymerase II into a primary miRNA (pri-miRNA). The pri-miRNA is then processed by the Drosha-DGCR8 complex into a precursor miRNA (pre-miRNA), which is exported to the cytoplasm. In the cytoplasm, the pre-miRNA is further cleaved by the Dicer enzyme, with the assistance of the Argonaute (Ago) proteins, to form a mature miRNA. This miRNA is incorporated into the RNA-induced silencing complex (miRISC), which includes Ago1-4 proteins. The miRISC complex can inhibit translation initiation through its interaction with eukaryotic initiation factors (eIFs), particularly eIF4F and eIF4A, or stimulate mRNA decay by recruiting the GW182 protein, which in turn associates with the PAN2-PAN3 and CCR4-NOT deadenylation complexes, leading to the shortening of the poly(A) tail and degradation of the target mRNA. Created with BioRender.com. (Retrieved from https://app.biorender.com/biorender-templates, accessed on 30 January 2024).

Figure 2

Characterization of brain-derived extracellular vesicles. Brain-derived extracellular vesicles enable cell-to-cell communication between different cell types in the brain as well as in the periphery. Extracellular vesicles can originate in neurons (NDEVs), astrocytes (ADEVs), and microglia (MDEVs). These vesicles can shuttle across the blood–brain barrier and enter the body’s circulation. Listed are the markers specific to each cell type that have been used to isolate extracellular vesicles from solution. Created with BioRender.com. (Retrieved from https://app.biorender.com/biorender-templates, accessed on 30 January 2024).

Figure 3

Modulation of miRNA function: endogenous expression, inhibition, and restoration strategies. This figure delineates three key approaches to modulating miRNA activity. On the left, ‘Endogenous miRNA expression’ illustrates a native miRNA being transcribed and subsequently leading to gene regulation through interaction with target mRNA. The middle panel, titled ‘Inhibition of endogenous miRNA by anti-miR’, depicts the process of an anti-miR molecule binding to and inhibiting an endogenous miRNA, thereby preventing it from exerting its gene regulatory function. The rightmost panel, ‘Overexpression of miRNA by miRNA mimic’, shows a miRNA mimic being introduced to overexpress a specific miRNA, leading to gene regulation. This schematic representation highlights the potential of manipulating miRNA levels and activity, either by inhibiting their function to upregulate gene expression or by mimicking their activity to downregulate gene expression in various therapeutic contexts. Created with BioRender.com.

Figure 4

Methodological framework for miRNA biomarker discovery in depression. This figure delineates a structured approach for the identification and analysis of circulating miRNAs as potential biomarkers in the context of MDD. The process begins with the collection of plasma/serum samples from both patients diagnosed with MDD and healthy control subjects. Step 1 involves the isolation of circulatory RNA from these samples, which is then subjected to microRNA sequencing (Step 2), a critical phase where the miRNAs are identified and quantified. In Step 3, the sequencing data undergo rigorous analysis. Step 4 involves statistical analysis to detect miRNAs whose expression levels significantly differ between the two groups. Biomarker identification (Step 5) is achieved through the comparison of miRNA expression profiles, leading to the selection of candidate miRNAs for further validation. Pathway analysis (Step 6) is then conducted to understand the biological pathways affected by the dysregulated miRNAs, followed by a detailed biological interpretation (Step 7) to elucidate their potential roles in the pathophysiology of MDD. This comprehensive protocol aims to enhance the understanding of miRNA functions in MDD and support the development of new therapeutic strategies. C = Control/healthy individuals; P = Patients. Created with BioRender.com.

Figure 5

miRNA detection using a gold nanoparticle-based lateral flow assay. This figure presents the sequential steps of a lateral flow assay (LFA) for the detection of microRNA (miRNA). Step 1: A sample (blood, plasma/serum) containing miRNA is applied to the assay, where the miRNA binds to a thiol-GNP-tagged detection probe. Step 2: The conjugate of miRNA and detection probe migrates along the nitrocellulose membrane through capillary action. Step 3: Upon reaching the test line (T), the conjugate encounters a biotin-tagged capture probe bound to streptavidin, facilitating binding and indicating a positive result. Step 4: Any excess detection probe that does not bind to the miRNA continues to migrate to the control line (C), where it is captured by a biotin-tagged control probe bound to streptavidin, confirming the assay’s functionality. The presence of two distinct lines indicates a successful assay, with the test line corresponding to miRNA detection and the control line serving as a procedural control. The legends section defines the visual symbols used in the figure, such as the miRNA, gold nanoparticle, thiol, thiol-GNP-tagged detection probe, biotin, streptavidin, and the biotin-tagged capture and control probes. Created with BioRender.com.