Coordinated Messenger RNA/MicroRNA Changes in Fibroblasts of Patients with Major Depression

Abstract

Background Peripheral biomarkers for major psychiatric disorders have been an elusive target for the last half a century. Dermal fibroblasts are a simple, relevant, and much underutilized model for studying molecular processes of patients with affective disorders as they share considerable similarity of signal transduction with neuronal tissue. Methods Cultured dermal fibroblast samples from patients with Major Depressive Disorder (MDD) and matched controls (CNTR) (n=16 pairs, 32 samples) were assayed for genome wide mRNA expression using microarrays. In addition, a simultaneous qPCR-based assessment of >1,000 miRNA species was performed. Finally, to test the relationship between the mRNA-miRNA expression changes, the two datasets were correlated with each other. Results Our data revealed that MDD fibroblasts, when compared to matched controls, showed a strong mRNA gene expression pattern change in multiple molecular pathways, including cell-to-cell communication, innate/adaptive immunity and cell proliferation. Furthermore, the same patient fibroblasts showed altered expression of a distinct panel of 38 miRNAs, which putatively targeted many of the differentially expressed mRNAs. The miRNA-mRNA expression changes appeared to be functionally connected, as the majority of the miRNA and mRNA changes were in the opposite direction. Conclusions Our data suggest that a combined miRNA-mRNA assessments are informative about the disease process, and that analyses of dermal fibroblasts might lead to the discovery of promising peripheral biomarkers of MDD, which could be potentially used to aid the diagnosis and allow mechanistic testing of disturbed molecular pathways.

MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder

“…These data are in line with the literature suggesting that fibroblasts could be a useful peripheral model for studying molecular processes in patients with neuropsychiatric disorders (Akin et al, 2004;Johansson et al, 2011;Auburger et al, 2012;Garbett et al, 2014;Kalman et al, 2014). In fact, fibroblasts are maintained in cultures in a controlled, reproducible environment, and after several rounds of cell division they are minimally affected by confounding factors (e.g., lifestyle or medication use) to which, in contrast, PBCs are exposed (Akin et al, 2004;Auburger et al, 2012;Garbett et al, 2014;Kalman et al, 2014).…”

MicroRNAs as biomarkers of resilience or vulnerability to stress

“…It is reasonable to expect that two weeks of recovery from stress affects a very different set of microRNAs than a timepoint more proximal to stress termination, such as the 24 h timepoint studied here. Recently, transcriptomic analysis of fibroblasts revealed a differential regulation of a panel of microRNAs and their targeted mRNAs between individuals with major depressive disorder and normal controls (Garbett et al, 2015). Thus, there is strong potential for the development of microRNAs as biomarkers for stress-related disease.…”

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders

“…Since TROY is a major partner of the Lingo-1/NgR/TROY complex, and considering the significant upregulation reported in the CA1, with no change in the CA3 of schizophrenia patients (Fernandez-Enright et al, 2014), additional mechanisms may be involved in the regulation of this protein which will need to be further investigated. Furthermore, a significant downregulation of TROY gene expression was found in the fibroblasts of major depressive disorder patients compared to matched healthy controls (Garbett et al, 2014), further implicating the Lingo-1/NgR/TROY complex in a wider variety of neuropsychiatric disorders.…”