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.

Salivary exosomal PSMA7: a promising biomarker of inflammatory bowel disease

“…In that study, in peripheral blood cells and fibroblasts collected from patients, the proteasome was shown to be responsible for the degradation of proteins and to control autoimmune disorders and immune tolerance. These functions are also relevant to disorders of the digestive system (Minelli et al, 2015 ).…”

Extracellular Vesicles with Possible Roles in Gut Intestinal Tract Homeostasis and IBD

“…In 2017, Zheng et al investigated the high sensibility of salivary exosomal PSMA7 on IBD diagnosis [121]. This study identified the proteins within EVs by using a liquid chromatograph-mass spectrometer, and PSMA7 was shown to be associated with inflammation and immune response as well as depressive disorder in many studies [122,123]. Rab proteins of the GTPase family are involved in selective packaging and docking at the plasma membranes of EVs [124].…”

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

“…To the best of our knowledge, only one study deals with AD response in HDF from AD-responder patients as compared to AD-resistant patients (defined as the failure to respond to two or more different classes of ADs and to a tricyclic AD drugs) [ 50 ]. They used HDF from a subpopulation of their cohort to study the link between PSMD13 ( gene encoding a key protein in the ubiquitin-proteasome complex) polymorphism (rs3817629) and the cognate mRNA expression.…”

“…They used HDF from a subpopulation of their cohort to study the link between PSMD13 ( gene encoding a key protein in the ubiquitin-proteasome complex) polymorphism (rs3817629) and the cognate mRNA expression. They showed that the double homozygous recessive GG carrier gene patients (4%) present a greater risk of AD resistance and have a diminished PSMD13 mRNA expression in HDF [ 50 ].…”