Abstract
An emerging area of research into major mental illnesses is to investigate the formation of insoluble aggregates of specific proteins in the brains of patients with these conditions. These studies are normally based on examining insoluble protein in post mortem brain samples, but, for practical reasons, typically consider only one region of the brain per subject. Here, we tested post mortem brain samples from multiple brain regions of various individuals, which included patients with major depressive disorder, schizophrenia and victims of suicide. Samples from patients with Alzheimer’s disease and control individuals were used for comparison. Notably, 20 tissue samples were available from across the brain of one individual who had both schizophrenia and Alzheimer’s disease. Consistently, while insolubility of DISC1 (Disrupted in Schizophrenia 1), CRMP1 (Collapsin Response Mediator Protein 1) and/or TRIOBP-1 (Trio and F-actin Binding Protein, isoform 1) were often present in multiple brain regions, this was not homogenous across the brain. While this study looks at a relatively small number of subjects, and caution must be taken in over-generalising, it is possible that aggregation of these proteins spreads throughout the brain, in a similar manner to the staging seen in neurodegenerative disease. Previous studies may therefore have underestimated the prevalence of protein aggregation in mental illness, due to this heterogeneity of insoluble protein across the brain.
Similar content being viewed by others
Data availability
All data generated in this study is included in the manuscript or online supplementary material.
References
WHO. World Mental Health Report: Transforming Mental Health for all (World Health Organization, 2022).
Kendler, K. S., Gatz, M., Gardner, C. O. & Pedersen, N. L. A Swedish national twin study of lifetime major depression. Am. J. Psychiatry. 163, 109–114. https://doi.org/10.1176/appi.ajp.163.1.109 (2006).
Hilker, R. et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register. Biol. Psychiatry. 83, 492–498. https://doi.org/10.1016/j.biopsych.2017.08.017 (2018).
Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681. https://doi.org/10.1038/s41588-018-0090-3 (2018).
Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502–508. https://doi.org/10.1038/s41586-022-04434-5 (2022).
Bradshaw, N. J. & Korth, C. Protein misassembly and aggregation as potential convergence points for non-genetic causes of chronic mental illness. Mol. Psychiatry. 24, 936–951. https://doi.org/10.1038/s41380-018-0133-2 (2019).
Hui, K. K., Endo, R., Sawa, A. & Tanaka, M. A perspective on the potential involvement of impaired proteostasis in neuropsychiatric disorders. Biol. Psychiatry. 91, 335–345. https://doi.org/10.1016/j.biopsych.2021.09.001 (2022).
Ochneva, A. et al. Protein misfolding and aggregation in the brain: common pathogenetic pathways in neurodegenerative and mental disorders. Int. J. Mol. Sci. 23, 14498. https://doi.org/10.3390/ijms232214498 (2022).
Leliveld, S. R. et al. Insolubility of Disrupted-in-Schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J. Neurosci. 28, 3839–3845. https://doi.org/10.1523/JNEUROSCI.5389-07.2008 (2008).
Bader, V. et al. Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits. Hum. Mol. Genet. 21, 4406–4418. https://doi.org/10.1093/hmg/dds273 (2012).
Nucifora, L. G. et al. A mutation in NPAS3 that segregates with schizophrenia in a small family leads to protein aggregation. Mol. Neuropsychiatry. 2, 133–144. https://doi.org/10.1159/000447358 (2016).
Samardžija, B. et al. Protein aggregation of NPAS3, implicated in mental illness, is not limited to the V304I mutation. J. Pers. Med. 11, 1070. https://doi.org/10.3390/jpm11111070 (2021).
Zaharija, B. et al. TRIOBP-1 protein aggregation exists in both major depressive disorder and schizophrenia, and can occur through two distinct regions of the protein. Int. J. Mol. Sci. 23, 11048. https://doi.org/10.3390/ijms231911048 (2022).
Ottis, P. et al. Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive Disrupted-in-Schizophrenia 1 aggresomes. Biol. Psychiatry. 70, 604–610. https://doi.org/10.1016/j.biopsych.2011.03.027 (2011).
Nucifora, L. G. et al. Increased protein insolubility in brains from a subset of patients with schizophrenia. Am. J. Psychiat. 176, 730–743. https://doi.org/10.1176/appi.ajp.2019.18070864 (2019).
Samardžija, B. et al. Co-aggregation and parallel aggregation of specific proteins in major mental illness. Cells 12, 1848. https://doi.org/10.3390/cells12141848 (2023).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 24, 197–211. https://doi.org/10.1016/s0197-4580(02)00065-9 (2003).
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H. & Del Tredici, K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404. https://doi.org/10.1007/s00401-006-0127-z (2006).
Bradshaw, N. J. et al. Aggregation of the protein TRIOBP-1 and its potential relevance to schizophrenia. PLOS One. 9, e111196. https://doi.org/10.1371/journal.pone.0111196 (2014).
Trossbach, S. V. et al. Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol. Psychiatry. 21, 1561–1572. https://doi.org/10.1038/mp.2015.194 (2016).
Young-Pearse, T. L., Suth, S., Luth, E. S., Sawa, A. & Selkoe, D. J. Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. J. Neurosci. 30, 10431–10440. https://doi.org/10.1523/jneurosci.1445-10.2010 (2010).
Shahani, N. et al. DISC1 regulates trafficking and processing of APP and Aβ generation. Mol. Psychiatry. 20, 874–879. https://doi.org/10.1038/mp.2014.100 (2015).
Deng, Q. S. et al. Disrupted-in-schizophrenia-1 attenuates amyloid-β generation and cognitive deficits in APP/PS1 transgenic mice by reduction of β-site APP-cleaving enzyme 1 levels. Neuropharmacology 41, 440–463. https://doi.org/10.1038/npp.2015.164 (2016).
Moda, F. et al. Secondary protein aggregates in neurodegenerative diseases: almost the rule rather than the exception Front. Biosci. (Landmark Ed). 28, 255. https://doi.org/10.31083/j.fbl2810255 (2023).
Kennis, M. et al. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol. Psychiatry. 25, 321–338. https://doi.org/10.1038/s41380-019-0585-z (2020).
Kato, T. & Duman, R. S. Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: convergent mechanisms. https://doi.org/10.1016/j.pbb.2019.172827. (2020).
Cui, L. et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal. Transduct. Target. Ther.. 9, 30. https://doi.org/10.1038/s41392-024-01738-y (2024).
Gray, J. P., Müller, V. I., Eickhoff, S. B. & Fox, P. T. Multimodal abnormalities of brain structure and function in major depressive disorder: A meta-analysis of neuroimaging studies. Am. J. Psychiatry. 177, 422–434. https://doi.org/10.1176/appi.ajp.2019.19050560 (2020).
Boldrini, M. et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. Biol. Psychiatry. https://doi.org/10.1016/j.biopsych.2018.12.022 (2019).
Underwood, M. D. et al. A stress protein–based suicide prediction score and relationship to reported early-life adversity and recent life stress. Int. J. Neuropsychopharmacol. 26, 501–512. https://doi.org/10.1093/ijnp/pyad025 (2023).
Zhu, Z. & Reiser, G. The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases. Neurochem. Int. 115, 69–79. https://doi.org/10.1016/j.neuint.2018.02.006 (2018).
Dean, B., Tsatsanis, A., Lam, L. Q., Scarr & Duce, J. A. Changes in cortical protein markers of iron transport with gender, major depressive disorder and suicide. World J. Biol. Psychiatry. 21, 119–126. https://doi.org/10.1080/15622975.2018.1555377 (2020).
Fatemi, S. H., Folsom, T. D., Eschenlauer, A., Chekouo, T. & Impaired aggrephagy interrupted vesicular trafficking, and cellular stress, lead to protein aggregation, and synaptic dysfunction in cerebellum of children and adults with idiopathic autism. Cerebellum 24, 140. https://doi.org/10.1007/s12311-025-01880-5 (2025).
Pils, M. et al. Disrupted-in-schizophrenia 1 (DISC1) protein aggregates in cerebrospinal fluid areelevated in first-episode psychosis patients. J. Neuropsychiatry Clin. Neurosci. 77, 665–671. https://doi.org/10.1111/pcn.13594 (2023).
Pavešić Radonja, A., Blazević Zelić, S., Rubeša, G. & Bradshaw, N. J. Symptom severity in schizophrenia patients with NPAS3, dysbindin-1 and/or TRIOBP protein pathology in their blood serum: a PANSS-based follow up study. Psychiatria Danubina. 35, 180–186. https://doi.org/10.24869/psyd.2023.180 (2023).
Nucifora, L. G. et al. Protein aggregation identified in olfactory neuronal cells is associated with cognitive impairments in a subset of living schizophrenia patients. Mol. Psychiatry. https://doi.org/10.1038/s41380-025-02956-8 (2025).
Zhu, C. Y., Shen, Y. & Xu, Q. Propagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits. Neuroscience 291, 301–316. https://doi.org/10.1016/j.neuroscience.2015.02.016 (2015).
Bader, V., Ottis, P., Pum, M., Huston, J. P. & Korth, C. Generation, purification, and characterization of cell-invasive DISC1 protein species. J. Vis. Exp. e4132. https://doi.org/10.3791/4132 (2012).
Zhu, S., Abounit, S., Korth, C. & Zurzolo, C. Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine. Open. Biol. 7, 160328. https://doi.org/10.1098/rsob.160328 (2017).
Palkovits, M. Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res. 59, 449–450 https://doi.org/10.1016/0006-8993(73)90290-4 (1973).
Palkovits, M. in In General Neurochemical Techniques Neuromethods. 1–17 (eds Alan, A., Boulton, Glen, B. & Baker) (Humana, 1985).
Marley, A. & von Zastrow, M. DISC1 regulates primary cilia that display specific dopamine receptors. PLoS One. 5, e10902. https://doi.org/10.1371/journal.pone.0010902 (2010).
Bradshaw, N. J. et al. An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure. J. Biol. Chem. 292, 9583–9598. https://doi.org/10.1074/jbc.M116.767939 (2017).
Zaharija, B. & Bradshaw, N. J. Aggregation of disrupted in schizophrenia 1 arises from a central region of the protein. Prog. Neuropsychopharmacol. Biol. Psychiatry. 130, 110923. https://doi.org/10.1016/j.pnpbp.2023.110923 (2024).
Acknowledgements
We thank Dr Beti Zaharija, Maja Juković, Matea Kršanac and Elizabeth Bradshaw for technical assistance and proof reading of the manuscript.
Funding
This work was supported by the Croatian Science Foundation (IP-2022-10-2745 & DOK-2020-01-8580), the Alexander von Humboldt Foundation (1142747-HRV-IP), the National Brain Program of the Hungarian Academy of Sciences (NAP3) 2022 (NAP2022-I-4/2022) and the Semmelweis University Thematic Excellence Programme 2021 (TKP 2021 EGA-25).
Author information
Authors and Affiliations
Contributions
Conceptualization, BS, MP & NJB; Data curation, BS, ÉR, MP and NJB; Formal analysis, BS and NJB; Funding acquisition, MP and NJB; Investigation, BS; Methodology, BS, ÉR, MP and NJB; Project administration, MP and NJB; Resources, ÉR and MP; Supervision, NJB; Visualization, BS and NJB; Writing—original draft, NJB; Writing—review and editing, BS, ÉR and MP. All authors have read and agreed to the published version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Samardžija, B., Renner, É., Palkovits, M. et al. Levels of aggregation of proteins related to mental illness, assayed by insolubility, vary across the brains of individuals. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35767-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-35767-0
