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

Overview

Authors: Cristina Ulecia-Morón1,2, Álvaro G Bris1,2, Lucía Inglada-Pérez3, Luis F Callado2,4,5, J Javier Meana2,4,5, David Martín-Hernández1,2, Karina S MacDowell1,2, Elena Figuero6, Javier R Caso1,2, Juan C Leza1,2
ORCID iDs: Cristina Ulecia-Morón, Álvaro G Bris, Lucía Inglada-Pérez, Luis F Callado, J Javier Meana, David Martín-Hernández, Karina S MacDowell, Elena Figuero, Javier R Caso, Juan C Leza
  1. Department of Pharmacology and Toxicology, Faculty of Medicine, University Complutense Madrid (UCM); Research Institute of Hospital 12 de Octubre (Imas12); University Institute of Research in Neurochemistry of the UCM (IUIN-UCM), Madrid, Spain
  2. Biomedical Research Network Centre in Mental Health, Institute of Health Carlos III (CIBERSAM, ISCIII), Madrid, Spain
  3. Department of Statistics and Operational Research, Faculty of Medicine, UCM, Madrid, Spain
  4. Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Bizkaia Spain
  5. BioBizkaia Health Research Institute, Barakaldo, Bizkaia Spain
  6. ETEP (Etiology and Therapy of Periodontal and Peri-implant Diseases) Research Group; Department of Dental Clinical Specialties, Faculty of Dentistry, UCM, Madrid, Spain
Institutions: Universidad Complutense de Madrid (Spain); Instituto de Salud Carlos III (Spain); Research Institute Hospital 12 de Octubre (Spain); Centro de Investigación Biomédica en Red de Salud Mental (Spain); University of the Basque Country (Spain)
Journal: Molecular biomedicine, volume 7, issue 1, article 138
Dates: received 13 October 2025; accepted 6 July 2026; published online 17 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s43556-026-00514-4 · PMID 42606669 · PMCID PMC13481630 · OpenAlex W7203588260
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: histology / microscopy (modality), human (organism), depression (population), schizophrenia / psychosis (population), cellular / molecular (subfield)
Methods: Statistics, Machine learning, Connectivity
Keywords: Neuroinflammation, Autophagy, UPR, Depression, Schizophrenia, Postmortem brain tissue
MeSH: Major Depressive Disorder*, Prefrontal Cortex*, Schizophrenia*, Transcription, Genetic*, Adult, Aged, Autophagy, Female, Humans, Male, Middle Aged, Protein Serine-Threonine Kinases, Signal Transduction, Unfolded Protein Response (* major topic)
Topic: Tryptophan and brain disorders (Biological Psychiatry, Neuroscience), according to OpenAlex
Funding: Agencia Estatal de Investigación (PID2022-137932NB-I00, PID2023-146894NB-I00, PID2019-109033RB-I00, PID2020-113103RB-I00); Instituto de Salud Carlos III (PI24/01875, CB/07/09/0026)
Citations: not cited yet (Europe PMC); 76 references in the paper

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s43556-026-00514-4.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The data supporting the findings of this study are not openly available due to the sensitive nature of individual-level human postmortem brain data and associated clinical and postmortem metadata. De-identified data may be made available from the corresponding authors upon request, subject to applicable ethical, legal, and institutional requirements. Data are stored in controlled-access institutional repositories at the Universidad Complutense de Madrid.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 6 keywords, 14 MeSH terms, 2 funders, 76 references.

Cite

This paper

Ulecia-Morón, C., Bris, Á. G., Inglada-Pérez, L., Callado, L. F., Meana, J. J., Martín-Hernández, D., MacDowell, K. S., Figuero, E., Caso, J. R., & Leza, J. C. (2026). Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects. Molecular biomedicine, 7(1), 138. https://doi.org/10.1186/s43556-026-00514-4

BibTeX

@article{uleciamoron2026transcription,
author = {Ulecia-Morón, Cristina and Bris, Álvaro G and Inglada-Pérez, Lucía and Callado, Luis F and Meana, J Javier and Martín-Hernández, David and MacDowell, Karina S and Figuero, Elena and Caso, Javier R and Leza, Juan C},
title = {{Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects}},
journal = {Molecular biomedicine},
year = {2026},
month = aug,
volume = {7},
number = {1},
pages = {138},
publisher = {Springer},
issn = {2662-8651},
doi = {10.1186/s43556-026-00514-4},
url = {https://doi.org/10.1186/s43556-026-00514-4},
pmid = {42606669},
pmcid = {PMC13481630}
}

RIS

TY - JOUR
AU - Ulecia-Morón, Cristina
AU - Bris, Álvaro G
AU - Inglada-Pérez, Lucía
AU - Callado, Luis F
AU - Meana, J Javier
AU - Martín-Hernández, David
AU - MacDowell, Karina S
AU - Figuero, Elena
AU - Caso, Javier R
AU - Leza, Juan C
TI - Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects
T2 - Molecular biomedicine
J2 - Mol Biomed
PY - 2026
DA - 2026/08/17
VL - 7
IS - 1
SP - 138
SN - 2662-8651
PB - Springer
DO - 10.1186/s43556-026-00514-4
UR - https://doi.org/10.1186/s43556-026-00514-4
LA - en
ER -

CSL-JSON

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