Abstract
Understanding the pathophysiological substrates of schizophrenia is a major challenge for current neuropsychiatric research. As part of a set of multi-omics experiments, we performed an extensive case-control proteomics study on 192 post-mortem tissue sections from prefrontal cortex from 96 individuals, including 47 cases with schizophrenia and 49 healthy controls. Using two independently measured cortical datasets, we identified 387 proteins differentially expressed between schizophrenia cases and controls at a 5% FDR threshold. This significantly regulated set of proteins contains genes located in GWAS-identified schizophrenia loci and proteins identified by pQTL analysis. Gene ontology analysis using GOAT provided evidence for regulation of several major protein categor…
Abstract
Understanding the pathophysiological substrates of schizophrenia is a major challenge for current neuropsychiatric research. As part of a set of multi-omics experiments, we performed an extensive case-control proteomics study on 192 post-mortem tissue sections from prefrontal cortex from 96 individuals, including 47 cases with schizophrenia and 49 healthy controls. Using two independently measured cortical datasets, we identified 387 proteins differentially expressed between schizophrenia cases and controls at a 5% FDR threshold. This significantly regulated set of proteins contains genes located in GWAS-identified schizophrenia loci and proteins identified by pQTL analysis. Gene ontology analysis using GOAT provided evidence for regulation of several major protein categories, emphasizing downregulation of mitochondrial oxidative respiration, ribosomes and the proteasome, upregulation of kinases and (small) GTPases. SynGO analysis supports the notion of synaptic dysfunction in schizophrenia, with major regulators of pre- and postsynaptic function compromised. Our findings highlight the complex molecular dysregulation in schizophrenia, with mitochondrial function downregulated versus signaling and trafficking upregulated, and synapse function disrupted; in combination with prior avenues of research, these finding support a role for energy deficits compromising highly ATP dependent neuronal function as a target for therapeutic interventions.
Data availability
The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository75 with the dataset identifier PXD058441. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the Dutch Research Council (NWO) research programme sectorplannen Biologie (51499 to F.K.), the Swedish Research Council (Vetenskapsrådet) (D0886501 to P.F.S.), the IDeA COBRE award from the National Institute of General Medical Sciences (P30 GM103328 to C.A.S.), the European Research Council advanced grant (ERC-2018-AdG GWAS2FUNC 834057 to W.P.L.). The authors thank the Netherlands Brain Bank (Amsterdam, the Netherlands) for supplying human brain tissue. The authors gratefully acknowledge contributions of the Cuyahoga County Medical Examiner’s Office, Cleveland, OH, USA, and the families of the deceased.
Author information
Authors and Affiliations
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, Netherlands
Frank Koopmans, Wei-Ping Li, Remco V. Klaassen, Yvonne Gouwenberg & August B. Smit 1.
Department of Pathology, Amsterdam University Medical Center (UMC), Amsterdam, Netherlands
Anke A. Dijkstra 1.
Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
Anke A. Dijkstra 1.
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, Netherlands
Wei-Ping Li 1.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Shuyang Yao, Robert Karlsson & Patrick F. Sullivan 1.
Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden
Lisa Bast & Jens Hjerling-Leffler 1.
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, Netherlands
Matthijs Verhage 1.
Department of Human Genetics, Amsterdam University Medical Center (UMC), Amsterdam, Netherlands
Matthijs Verhage 1.
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
Andrew J. Dwork 1.
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA
Craig A. Stockmeier 1.
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
Patrick F. Sullivan
Authors
- Frank Koopmans
- Anke A. Dijkstra
- Wei-Ping Li
- Remco V. Klaassen
- Yvonne Gouwenberg
- Shuyang Yao
- Lisa Bast
- Matthijs Verhage
- Robert Karlsson
- Andrew J. Dwork
- Craig A. Stockmeier
- Jens Hjerling-Leffler
- Patrick F. Sullivan
- August B. Smit
Contributions
A.B.S., F.K., and P.F.S. designed the experiments. A.A.D., R.V.K., and Y.G. performed the experiments. F.K., W.P.L., S.Y., R.K., L.B., and P.F.S. performed data analysis. F.K. and A.B.S. interpreted the results. A.J.D. and C.A.S. provided samples, and A.A.D. performed the pathological characterization. A.B.S. and F.K. wrote the manuscript; P.F.S., M.V., and J.H.L. made intellectual contributions and contributed to the writing of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Correspondence to August B. Smit.
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P.F.S. reports the following potentially competing financial interest: Neumora Therapeutics (advisory committee, shareholder). To the best of his knowledge, these are unrelated to this paper/project. The remaining authors declare no competing interests.
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Koopmans, F., Dijkstra, A.A., Li, WP. et al. Human brain prefrontal cortex proteomics identifies compromised energy metabolism and neuronal function in Schizophrenia. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68950-y
Received: 30 November 2024
Accepted: 21 January 2026
Published: 29 January 2026
DOI: https://doi.org/10.1038/s41467-026-68950-y