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Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

ABSTRACT: Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance-related processes may be involved in several phenotypes, including the TRD.

SUBMITTER: Minelli A

PROVIDER: S-EPMC5068581 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

Minelli A A Magri C C Barbon A A Bonvicini C C Segala M M Congiu C C Bignotti S S Milanesi E E Trabucchi L L Cattane N N Bortolomasi M M Gennarelli M M

Translational psychiatry 20151201

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the po ...[more]

PMID: 26624926

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

Dataset Information

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

Publications

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

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