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Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

Molecular Psychiatry volume 13, pages 1102–1117 (2008)Cite this article

Abstract

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

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Acknowledgements

Post-mortem brains were donated by the Stanley Foundation Brain Bank Consortium courtesy of Drs Llewellyn B Bigelow, Juraj Cervenak, Mary M Herman, Thomas M Hyde, Joel Kleinman, Jose D Paltan, Robert M Post, E Fuller Torrey, Maree J Webster and Robert Yolken. We also acknowledge the contribution of the SMRI in providing access to the Stanley Genomic Database. We thank Professor Peter Hall, Department of Pathology, Queens University Belfast, for his useful and insightful discussions. In addition, we thank Lance Hudson for technical assistance in 2-DE image analysis. Access to and use of MS instrumentation of Conway Institute is gratefully acknowledged and we thank Dr Niaobh O’Donoghue, Kaspar Pedersen and Kieran Wynne for their technical assistance in mass spectrometry. Additionally, we thank Matt Sullivan and the proteomics informatics group (http://proteomics.ucd.ie) for use of their Proline software. This work was funded by a Wellcome Trust project award to DRC, The Stanley Medical Research Institute and Science Foundation Ireland under Grant no. 04/RPI/B499 to MJD. RW received financial support from ARC and MRC.

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Authors and Affiliations

  1. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland

    K Pennington, J English & D R Cotter

  2. Proteome Research Centre, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

    K Pennington & M J Dunn

  3. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

    C L Beasley

  4. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons, Dublin, Ireland

    P Dicker

  5. School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

    A Fagan

  6. Division of Psychological Medicine, King's College, Section of Stress, Psychiatry and Immunology, Institute of Psychiatry, London, UK

    C M Pariante

  7. Kennedy Institute of Rheumatology Division, Imperial College, London, UK

    R Wait

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Pennington, K., Beasley, C., Dicker, P. et al. Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder. Mol Psychiatry 13, 1102–1117 (2008). https://doi.org/10.1038/sj.mp.4002098

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