A microRNA plays role in major depression
A tiny RNA appears to play a role in producing major depression, the mental disorder that affects as many as 250 million people a year worldwide. Major depression, formally known as major depressive disorder, or MDD, brings increased risk of suicide and is reported to cause the second-most years of disability after low-back pain.
Researchers have found that amounts of this microRNA are significantly elevated in the brains of experimental rats with induced depression from corticosterone treatment, in the post-death brains of humans diagnosed with MDD and in peripheral blood serum from living patients with MDD.
This microRNA — miR-124-3p — is thus a potential therapeutic target for novel drug development, and it can serve as a putative biomarker for MDD pathogenesis.
Micro RNAs, or miRNAs, interact with messenger RNA after the miRNA is exported from the cell nucleus and processed by a team of enzymes. MiRNAs are robust players of gene regulation in cells, and there are more than 1,300 different miRNAs at work in the brain.
In previous work, researchers had seen that a set of miRNAs were coordinately regulated in the prefrontal cortex of the brains of MDD subjects. The prefrontal cortex, known for controlling the executive function of the brain, is critically involved in the response to stress, by regulating the endocrine glands known as the hypothalamic-pituitary-adrenal axis. The adrenal gland produces the stress hormone cortisol in humans and corticosterone in rodents.
To see if stress plays a role in the coordinated regulation of prefrontal cortex miRNAs, the researchers then turned to a rat depression model. They found that rats treated with corticosterone to induce depression-like behavior showed coordinated dysregulation of miRNAs in the prefrontal cortex, and the most significantly affected miRNA was miR-124-3p.
The current paper examined the relevance of miR-124-3p in MDD pathogenesis. Using computer analysis of genome sequences, the researchers identified eight highly potential target genes for binding by miR-124-3p, genes whose function is also reported to be critical in brain physiology during stress and MDD pathogenesis.
Four of these potential target genes were significantly down-regulated in the prefrontal cortex of corticosterone-treated rats, and this down-regulation inversely correlated with miR-124-3p levels. They also showed that the four genes that were significantly down-regulated have evolutionarily conserved miR-124-3p binding sites across a wide range of higher vertebrate species.
But what does this mean for humans? Well I’m glad you asked.
In post-mortem brains of 15 controls and 15 MDD subjects, the MDD group showed significant increase in the expression of miR-124-3p, and expression of three of the potential target genes was significantly lower.The level of miR-124-3p was significantly higher in the serum of 18 antidepressant-free MDD patients, as compared with 17 healthy controls.
“This is the first comprehensive and mechanistic study at in-vitro and in-vivo levels which demonstrates that, not only are there consistent depression-associated changes in the expression of miR-124-3p across different species, but also the genes that are targets of this miRNA are highly dysregulated, showing altered response at functional level.”
Roy, B., Dunbar, M., Shelton, R., & Dwivedi, Y. (2016). Identification of microRNA-124-3p as a Putative Epigenetic Signature of Major Depressive Disorder Neuropsychopharmacology DOI: 10.1038/npp.2016.175