Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects

Abstract

Abstract Major depressive disorder (MDD) and schizophrenia (SCZ) are severe psychiatric disorders, the molecular mechanisms of which remain incompletely understood. Increasing evidence implicates neuroinflammatory signaling, autophagy dysregulation, and unfolded protein response (UPR) alterations in their pathophysiology. Here, we analyzed dorsolateral prefrontal cortex (DLPFC) samples from postmortem human brains of 28 MDD subjects, 28 SCZ subjects, and 28 matched controls. Gene expression levels of key inflammatory, autophagy, and UPR-related markers were assessed by RT-qPCR, while selected proteins were quantified by Western blot and ELISA. Logistic and linear regression models were applied to evaluate disease-associated alterations and the influence of sex, age, and cause of death. Transcriptional analyses revealed pathway-specific alterations in both disorders, with IRE1α emerging as the most consistently upregulated marker across MDD and SCZ. Sex-stratified analyses indicated that risk-associated transcriptional changes were more prominent in men with MDD, whereas women with SCZ showed broader transcriptional alterations. Age-related effects were mainly detected at the mRNA level, particularly in autophagy-related genes. In contrast, protein analyses showed a generalized downregulation of several inflammatory (AIM2, NLRP3), autophagy (ATG7, mTOR, RAB5A), and UPR-related (IRE1α) proteins in both disorders. In SCZ subjects who died by suicide, increased IL18 , CASPASE-5 , and IRE1α transcription, together with increased CASPASE-8 protein levels, suggested enhanced inflammatory and stress-related signaling. Overall, these findings reveal a marked transcription-protein dissociation in key cellular stress pathways in the DLPFC of MDD and SCZ subjects, supporting multilayer regulation of inflammatory, autophagy-related, and UPR responses in the psychiatric brain.