title: Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors.
abstract: Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tissues. We examined the effects of two metabolic stressors, galactose (GAL) or reduced lipids (RL), on the transcriptome and miRNome of human fibroblasts from 16 pairs of patients with MDD and matched healthy controls (CNTR). Our results demonstrate that both MDD and CNTR fibroblasts had a robust molecular response to GAL and RL challenges. Most importantly, a significant part (messenger RNAs (mRNAs): 26-33%; microRNAs (miRNAs): 81-90%) of the molecular response was only observed in MDD, but not in CNTR fibroblasts. The applied metabolic challenges uncovered mRNA and miRNA signatures, identifying responses to each stressor characteristic for the MDD fibroblasts. The distinct responses of MDD fibroblasts to GAL and RL revealed an aberrant engagement of molecular pathways, such as apoptosis, regulation of cell cycle, cell migration, metabolic control and energy production. In conclusion, the metabolic challenges evoked by GAL or RL in dermal fibroblasts exposed adaptive dysfunctions on mRNA and miRNA levels that are characteristic for MDD. This finding underscores the need to challenge biological systems to bring out disease-specific deficits, which otherwise might remain hidden under resting conditions.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Garbett
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Vereczkei
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Department of Psychiatry, University of Szeged, Szeged, Hungary.
authors.forename: S
authors.initials: S
authors.lastname: Kálmán
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
authors.forename: Ž
authors.initials: Ž
authors.lastname: Korade
authors.affiliation: Department of Psychiatry, University of Alabama, Birmingham, AL, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Shelton
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University, Nashville, TN, USA [2] Department of Psychiatry, University of Szeged, Szeged, Hungary [3] Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
authors.forename: K
authors.identifier: 0000000255210254
authors.initials: K
authors.lastname: Mirnics
mesh_terms: D000328:Adult; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger