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Mass Spectrometry based identification of site-specific proteomic alterations and potential pathways underlying the pathophysiology of schizophrenia

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Abstract

Background

Schizophrenia (SZ) is a complex multifactorial disorder that affects 1% of the population worldwide with no available effective treatment. Although proteomic alterations are reported in SZ however proteomic expression aberrations among different brain regions are not fully determined. Therefore, the present study aimed spatial differential protein expression profiling of three distinct regions of SZ brain and identification of associated affected biological pathways in SZ progression.

Methods and results

Comparative protein expression profiling of three distinct autopsied human brain regions (i.e., substantia nigra, hippocampus and prefrontal cortex) of SZ was performed with respective healthy controls. Using two-dimensional electrophoresis (2DE)-based nano liquid chromatography tandem mass spectrometry (Nano-LC MS /MS) analysis, 1443 proteins were identified out of which 58 connote to be significantly dysregulated, representing 26 of substantia nigra,14 of hippocampus and 18 of prefrontal cortex. The 58 differentially expressed proteins were further analyzed using Ingenuity pathway analysis (IPA). The IPA analysis provided protein-protein interaction networks of several proteins including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kb), extracellular signal regulated kinases 1/2 (ERK1/2), alpha serine / Threonine-protein kinase (AKT1), cellular tumor antigen p53 (TP53) and amyloid precursor protein (APP), holding prime positions in networks and interacts with most of the identified proteins and their closely interacting partners.

Conclusion

These findings provide conceptual insights of novel SZ related pathways and the cross talk of co and contra regulated proteins. This spatial proteomic analysis will further broaden the conceptual framework for schizophrenia research in future.

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Data Availability

All raw and supplementary data is available with submission.

Abbreviations

LC-MS/MS:

Liquid chromatography–mass spectrometry/ mass spectrometry

ERK1/2:

Extracellular signal regulated kinases 1/2

AKT:

Alpha serine / Threonine-protein kinase

APP:

Amyloid precursor protein

TNF:

Tumor necrosis factor

NF kb:

Nuclear factor kappa-light-chain-enhancer of activated B cells

MAPT:

Microtubule associated protein tau

PSEN1:

Presenilin 1

TP53:

Cellular tumor antigen p53

IL4:

Interleukin 4

IPA:

Ingenuity pathway analysis

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Acknowledgements

Medical Research Council (MRC) Sudden Death Brain and Tissue Bank, Department of Neuropathology, The University of Edinburgh, U.K. for providing brain specimens to Nikhat Ahmed. Ingenuity Pathway Analysis (IPA) for providing free trial version of the software. Higher education commission (HEC), Pakistan for providing financial support (Grant no. 20–560/ R&D/07) to Nikhat Ahmed.

Funding

The present work was supported by Grant no. 20–560/ R&D/07 to Nikhat Ahmed from Higher education commission (HEC), Pakistan,

Author information

Authors and Affiliations

  1. Neurochemistry Research Laboratory, Department of Biochemistry, University of Karachi, Karachi, 75270, Pakistan

    Ayesha Khan, Saadia Zahid, Beena Hasan & Nikhat Ahmed

  2. Neurobiology Research Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan

    Saadia Zahid

  3. Institute of Clinical Chemistry, University Medical Center, Robert-Koch-Str. 40, 37075, Göttingen, Göttingen, Germany

    Abdul R Asif

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  1. Ayesha Khan
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  4. Abdul R Asif
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Contributions

Nikhat Ahmed conceptualization, Ayesha Khan, Saadia Zahid, Beena Hasan, Abdul Rehman Asif methodology and investigation, Ayesha Khan, Saadia Zahid, Nikhat Ahmed contributed to writing/original draft preparation, Nikhat Ahmed funding. manuscript reviewed and edited by Nikhat Ahmed.

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Correspondence to Nikhat Ahmed.

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The authors declare no competing interests.

Ethics approval

This study has been performed in line with the permission of Ethical Review Board of University of Karachi, Karachi, Pakistan.

Consent to participate

Autopsied Brain samples of control and schizophrenia patients were obtained from Medical Research Council (MRC) Sudden Death Brain and Tissue Bank (SDBTB), Department of Neuropathology, The University of Edinburgh, U.K. The Edinburgh SDBTB provides an alternative model for brain donations postmortem and appropriate consent from next of kin of the deceased individual was taken after a sudden death.

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Khan, A., Zahid, S., Hasan, B. et al. Mass Spectrometry based identification of site-specific proteomic alterations and potential pathways underlying the pathophysiology of schizophrenia. Mol Biol Rep 50, 4931–4943 (2023). https://doi.org/10.1007/s11033-023-08431-3

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