title: 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.
authors.affiliation: Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Minelli
authors.affiliation: Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Brescia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Magri
authors.affiliation: Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Barbon
authors.affiliation: Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bonvicini
authors.affiliation: Psychiatric Hospital 'Villa Santa Chiara', Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Segala
authors.affiliation: Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Brescia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bignotti
authors.affiliation: Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.|Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Milanesi
authors.affiliation: Psychiatric Hospital 'Villa Santa Chiara', Verona, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Trabucchi
authors.affiliation: Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Cattane
authors.affiliation: Psychiatric Hospital 'Villa Santa Chiara', Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bortolomasi
authors.affiliation: Department of Molecular and Translational Medicine, Biology and Genetic Division, University of Brescia, Brescia, Italy.|Genetic Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gennarelli
mesh_terms: D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics*; D061218:Depressive Disorder, Treatment-Resistant / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*
chemical_list: C114476:PSMD9 protein, human; C488662:PSMA7 protein, human; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13