Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

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

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.

Trial registration: ClinicalTrials.gov NCT00021528.

Figures

Figure 1
Figure 1
Relative expression mRNA levels of PSMD13 rs3817629. Box-plots showing the median, quartiles and extreme values of relative expression of PSMD13 rs3817629 A allele carriers with respect to GG subjects. The bold lines represent median values, the box boundaries mark the 25th and 75th percentiles of each distribution, respectively. Whiskers, above and below the hinges, mark the largest and smallest observed values. (a) the analysis was performed in all subjects; (b) only in MDD group; (c) only in control group. '*' Indicates significant difference (P-value<0.05) computed by the Mann–Whitney U non-parametric test. MDD, major depressive disorder.
Figure 2
Figure 2
Relative expression mRNA levels of PSMD9 rs1043307. Box-plots showing the median, quartiles and extreme values of relative expression of PSMD9 rs1043307 in (a) MDD patients and controls; (b) in healthy subjects, TRD and non-TRD. The bold lines represent median values, the box boundaries mark the 25th and 75th percentiles of each distribution, respectively. Whiskers, above and below the hinges, mark the largest and smallest observed values, respectively. '**' Indicates significant difference (P-value<0.01), whereas '***' indicates a P-value <0.001, computed by the Kruskal–Wallis and Mann–Whitney U non-parametric tests.

References

    1. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40.
    1. Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Spencer D, Fava M. The STAR*D study: treating depression in the real world. Cleve Clin J Med 2008; 75: 57–66.
    1. Thomas L, Kessler D, Campbell J, Morrison J, Peters TJ, Williams C et al. Prevalence of treatment-resistant depression in primary care: cross-sectional data. Br J Gen Pract 2013; 63: e852–e858.
    1. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry 2007; 52: 46–54.
    1. Carvalho LA, Pariante CM. In vitro modulation of the glucocorticoid receptor by antidepressants. Stress 2008; 11: 411–424.
    1. Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K et al. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord 2013; 148: 136–140.
    1. Bufalino C, Hepgul N, Aguglia E, Pariante CM. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun 2013; 31: 31–47.
    1. Gomes AV. Genetics of proteasome diseases. Scientifica (Cairo) 2013; 2013: 637629.
    1. Lam YA, Pickart CM, Alban A, Landon M, Jamieson C, Ramage R et al. Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proc Natl Acad Sci USA 2000; 97: 9902–9906.
    1. Lee YH, Kim JH, Song GG. Pathway analysis of a genome-wide association study in schizophrenia. Gene 2013; 525: 107–115.
    1. Bousman CA, Chana G, Glatt SJ, Chandler SD, May T, Lohr J et al. Positive symptoms of psychosis correlate with expression of ubiquitin proteasome genes in peripheral blood. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1336–1341.
    1. Bousman CA, Chana G, Glatt SJ, Chandler SD, Lucero GR, Tatro E et al. Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: convergent pathway analysis findings from two independent samples. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 494–502.
    1. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22: 2718–2729.
    1. Vawter MP, Barrett T, Cheadle C, Sokolov BP, Wood WH 3rd, Donovan DM et al. Application of cDNA microarrays to examine gene expression differences in schizophrenia. Brain Res Bull 2001; 55: 641–650.
    1. Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 2005; 58: 85–96.
    1. Wong ML, Dong C, Maestre-Mesa J, Licinio J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008; 13: 800–812.
    1. Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013; 18: 497–511.
    1. Gragnoli C. Proteasome modulator 9 gene SNPs, responsible for anti-depressant response, are in linkage with generalized anxiety disorder. J Cell Physiol 2014; 229: 1157–1159.
    1. Mostafavi S, Battle A, Zhu X, Potash JB, Weissman MM, Shi J et al. Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing. Mol Psychiatry 2014; 19: 1267–1274.
    1. Mehta D, Menke A, Binder EB. Gene expression studies in major depression. Curr Psychiatry Rep 2010; 12: 135–144.
    1. Tylee DS, Kawaguchi DM, Glatt SJ. On the outside, looking in: a review and evaluation of the comparability of blood and brain "-omes". Am J Med Genet B Neuropsychiatr Genet 2013; 162B: 595–603.
    1. Garbett KA, Vereczkei A, Kalman S, Brown JA, Taylor WD, Faludi G et al. Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol Psychiatry 2014; 77: 256–265.
    1. Hayashi-Takagi A, Vawter MP, Iwamoto K. Peripheral biomarkers revisited: integrative profiling of peripheral samples for psychiatric research. Biol Psychiatry 2014; 75: 920–928.
    1. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58: 23–29.
    1. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59: 22–33, quiz 34-57.
    1. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
    1. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012; 22: 1790–1797.
    1. Garriock HA, Kraft JB, Shyn SI, Peters EJ, Yokoyama JS, Jenkins GD et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry 2010; 67: 133–138.
    1. Perlis RH, Moorjani P, Fagerness J, Purcell S, Trivedi MH, Fava M et al. Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study. Neuropsychopharmacology 2008; 33: 2810–2819.
    1. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002; 287: 1840–1847.
    1. Browning BL, Browning SR. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 2009; 84: 210–223.
    1. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
    1. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer data sets. Gigascience 2015; 4: 7.
    1. Garbett KA, Vereczkei A, Kalman S, Brown JA, Taylor WD, Faludi G et al. Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol Psychiatry 2015; 77: 256–265.
    1. Gabriela Nielsen M, Congiu C, Bortolomasi M, Bonvicini C, Bignotti S, Abate M et al. MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder. J Affect Disord 2015; 183: 179–186.
    1. Galecki P, Galecka E, Maes M, Orzechowska A, Berent D, Talarowska M et al. Vascular endothelial growth factor gene (VEGFA) polymorphisms may serve as prognostic factors for recurrent depressive disorder development Prog Neuropsychopharmacol. Biol Psychiatry 2013; 45: 117–124.
    1. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3: 1101–1108.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175–191.
    1. Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods 2009; 41: 1149–1160.
    1. Hollenhorst PC, Chandler KJ, Poulsen RL, Johnson WE, Speck NA, Graves BJ. DNA specificity determinants associate with distinct transcription factor functions. PLoS Genet 2009; 5: e1000778.
    1. Jolma A, Kivioja T, Toivonen J, Cheng L, Wei G, Enge M et al. Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities. Genome Res 2010; 20: 861–873.
    1. Yu S, Cui K, Jothi R, Zhao DM, Jing X, Zhao K et al. GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells. Blood 2011; 117: 2166–2178.
    1. Anacker C, Zunszain PA, Carvalho LA, Pariante CM. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011; 36: 415–425.
    1. Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 2014; 17: 1418–1428.
    1. Cattane N, Minelli A, Milanesi E, Maj C, Bignotti S, Bortolomasi M et al. Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. PLoS One 2015; 10: e0116686.
    1. Auburger G, Klinkenberg M, Drost J, Marcus K, Morales-Gordo B, Kunz WS et al. Primary skin fibroblasts as a model of Parkinson's disease. Mol Neurobiol 2012; 46: 20–27.
    1. van Deventer S, Neefjes J. The immunoproteasome cleans up after Inflammation. Cell 2010; 142: 517–518.
    1. Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F et al. Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 2010; 142: 613–624.
    1. Minelli A, Maffioletti E, Shiloh AR. Genetics of anxiety disorders, In: Anxiety disorders: Risk factors, Genetic Determinants and Cognitive-behavioral Treatment. Nova Science Publishers, Hauppauge, NY, USA, 2014.
    1. Hettema JM. What is the genetic relationship between anxiety and depression? Am J Med Genet C Semin Med Genet 2008; 148C: 140–146.
    1. Gatt JM, Burton KL, Williams LM, Schofield PR. Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res 2015; 60C: 1–13.
    1. Blanco C, Rubio J, Wall M, Wang S, Jiu CJ, Kendler KS. Risk factors for anxiety disorders: common and specific effects in a national sample. Depress Anxiety 2014; 31: 756–764.
    1. Akin D, Manier DH, Sanders-Bush E, Shelton RC. Decreased serotonin 5-HT2A receptor-stimulated phosphoinositide signaling in, fibroblasts from melancholic depressed patients. Neuropsychopharmacology 2004; 29: 2081–2087.
    1. Kalman S, Garbett KA, Vereczkei A, Shelton RC, Korade Z, Mirnics K. Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts. Exp Cell Res 2014; 320: 343–353.
    1. Licinio J, O'Kirwan F, Irizarry K, Merriman B, Thakur S, Jepson R et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol Psychiatry 2004; 9: 1075–1082.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere