Protein aggregation of DISC1, as assayed by insolubility, varies across the brain of an individual with schizophrenia and Alzheimer’s disease

Objective Subgroups of mental illness patients have been seen to display disturbed proteostasis, with specific proteins aggregating in their brain, which is generally determined by assaying protein insolubility in the post mortem samples. Such studies typically only look at one region of the brain, and therefore we aimed to determine the distribution of protein across a single brain, using this insolubility-based approach. Methods We looked at 20 post mortem tissue samples from across the brain of a single patient, with schizophrenia and Alzheimer’s disease, determined which protein(s) aggregated in his brain relative to controls, based on purification of insoluble protein fractions. The individual samples were then similarly analysed. Results Disrupted in Schizophrenia 1 (DISC1) protein was seen to be insoluble in the patient’s brain, however in a very heterogenous picture, with differences in insoluble DISC1 even between samples of the same region, but opposite hemispheres. Conclusions While caution must be taken in extrapolating from a single individual, this raises the possibility that aggregates of DISC1 may spread throughout the brain, as is the case for proteins in neurodegenerative disorders, and suggests that current studies looking at single brain regions may be underestimating the prevalence of protein aggregates in schizophrenia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Alexander von Humboldt Foundation (1142747-HRV-IP), the Croatian Science Foundation (IP-2018-01-9424 and DOK-2020-01-8580), and the Hungarian National Research, Development and Innovation Office (NKFIH 2017-1.2.1-NKP-2017-00002, National Brain Research Program NAP 2.0 and NAP2022-I-4/2022, National Brain Research Program NAP 3.0). None of the authors, nor their institutions, received payment or services from any other third party for any aspect of the submitted work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Committee of Science and Research Ethics of the Ministry of Health of Hungary gave ethical approval for the collection and distribution of samples used in this work (No. 6008/8/2002/ETT). The Regional Committee of Science and Research Ethics of the Semmelweis University gave ethical for the collection and distribution of samples used in this work (No. 32/1992/TUKEB). The Ethical Committee of the University of Rijeka, Department of Biotechnology gave ethical approval for this work (18.02.2022-Bradshaw). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.