An analysis of 84 post-mortem brains found altered cellular stress pathways in people with major depression or schizophrenia. RNA changes did not consistently line up with protein levels.
Researchers examined samples from the dorsolateral prefrontal cortex, a brain region involved in regulating cognitive and emotional processes. The study included 84 people: 28 with major depression. Another 28 had schizophrenia, and the remaining 28 were controls.
The research involved Universidad Complutense de Madrid, known as UCM, and the área de Salud Mental del CIBER, known as CIBERSAM. CIBERSAM researchers at Universidad del País Vasco also took part. First author Cristina Ulecia-Morón is a CIBERSAM researcher. The team examined pathways linked to inflammation and autophagy, the cell’s process for recycling damaged components. It also studied the endoplasmic reticulum’s response to misfolded proteins.
The RNA and protein results diverged. RNA levels of IRE1α, a component of the cellular response to misfolded proteins in the endoplasmic reticulum, were significantly higher in both diagnostic groups than in controls.
Selected genes showed increased expression across the pathways. Several measured proteins, by contrast, showed an overall decrease in both disorders. That gap means gene activity alone may not reveal how much of a protein is present. The researchers say the findings point to post-transcriptional regulation, which needs to be studied alongside RNA expression.
The pattern also varied by sex. Gene-expression changes were more prominent in men with major depression. Women with schizophrenia showed a greater number of changes. Age-related effects appeared mainly in gene expression, especially among genes linked to autophagy.
Among people with schizophrenia who had died by suicide, IL18 expression was higher. The same was true for caspase-5 and IRE1α. Caspase-8 protein levels were also elevated in this subgroup. The authors describe a distinct molecular pattern involving inflammation and cellular stress responses.
The study appeared in Molecular Biomedicine in 2026 under the title “Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects.” It was published in volume 7, issue 1, as article 138. The DOI is 10.1186/s43556-026-00514-4.
These post-mortem findings identify molecular associations. They do not establish that the changes cause either disorder. The work is fundamental research, not a clinical trial. It presents no diagnostic test and no treatment. The authors say further research is needed to establish the functional effects of the changes.
