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  • Original Research Article
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Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder

Abstract

Severe psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder are brain diseases of unknown origin. No biological marker has been documented at the pathological, cellular, or molecular level, suggesting that a number of complex but subtle changes underlie these illnesses. We have used proteomic technology to survey postmortem tissue to identify changes linked to the various diseases. Proteomics uses two-dimensional gel electrophoresis and mass spectrometric sequencing of proteins to allow the comparison of subsets of expressed proteins among a large number of samples. This form of analysis was combined with a multivariate statistical model to study changes in protein levels in 89 frontal cortices obtained postmortem from individuals with schizophrenia, bipolar disorder, major depressive disorder, and non-psychiatric controls. We identified eight protein species that display disease-specific alterations in level in the frontal cortex. Six show decreases compared with the non-psychiatric controls for one or more diseases. Four of these are forms of glial fibrillary acidic protein (GFAP), one is dihydropyrimidinase-related protein 2, and the sixth is ubiquinone cytochrome c reductase core protein 1. Two spots, carbonic anhydrase 1 and fructose biphosphate aldolase C, show increase in one or more diseases compared to controls. Proteomic analysis may identify novel pathogenic mechanisms of human neuropsychiatric diseases.

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References

  1. O'Farrell P . High resolution two-dimensional electrophoresis of proteins J Biol Chem 1975; 250: 4007–4021

    CAS  PubMed  Google Scholar 

  2. Comings DE . Two-dimensional gel electrophoresis of human brain proteins. III Genetic and non-genetic variations in 145 brains Clin Chem 1982; 28: 798–804

    CAS  PubMed  Google Scholar 

  3. Edgar PF, Schonberger SJ, Dean B, Faull RLM, Kydd R, Cooper GJS . A comparative proteome analysis of hippocampal tissue from schizophrenia and Alzheimer's disease individuals Mol Psychiatry 1999; 4: 173–178

    Article  CAS  PubMed  Google Scholar 

  4. Harrington M, Merril CR, Torrey EF . Differences in cerebrospinal fluid proteins between patients with schizophrenia and normal persons Clin Chem 1985; 31: 722–726

    CAS  PubMed  Google Scholar 

  5. Merril CR, Harrington MG . Use of two-dimensional electrophoretic protein maps in studies of schizophrenia Schizophr Bull 1988; 14: 249–254

    Article  CAS  PubMed  Google Scholar 

  6. Wildenauer DB, Korschenhausen D, Hoechtlen W, Ackenheil M, Kehl M, Lottspeich F . Analysis of cerebrospinal fluid from patients with psychiatric and neurological disorders by two-dimensional electrophoresis: identification of disease associated polypeptides as filbrin fragments Electrophoresis 1991; 12: 487–492

    Article  CAS  PubMed  Google Scholar 

  7. Johnson G, Brane D, Block W, van Kammen DP, Gurklis J, Peters JL et al. Cerebrospinal fluid protein variations in common to Alzheimer's disease and schizophrenia Appl Theo Electrophor 1992; 3: 47–53

    CAS  Google Scholar 

  8. James P . Of genomes and proteomes Biochem Biophys Res Commun 1997; 231: 1–6

    Article  CAS  PubMed  Google Scholar 

  9. Shevchenko A, Jensen ON, Podtelejnikov AV, Sagliocco F, Wilm M, Vorm O et al. Linking genome and proteome by mass spectrometry: large scale identification of yeast proteins from two-dimensional gels Proc Natl Acad Sci USA 1996; 93: 14440–14445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Anderson NL, Esquer-Blasco R, Hofmann J-P, Meheus L, Raymackers J, Steiner S et al. An updated two-dimensional gel database of rat liver proteins useful in gene regulation and drug effects studies Electrophoresis 1995; 16: 1977–1981

    Article  CAS  PubMed  Google Scholar 

  11. Johnston NL, Cervenak J, Shore D, Torrey EF, Yolken RH, the Stanley Neuropathology Consortium . Multivariate analysis of RNA levels from postmortem human brains as measured by three different methods of RT-PCR J Neurosci Meth 1997; 77: 83–92

    Article  CAS  Google Scholar 

  12. Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM . Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33 Nature 1995; 376: 509–514

    Article  CAS  PubMed  Google Scholar 

  13. Goshima Y, Kawakami T, Hori H, Sugiyama Y, Takasawa S, Hashimoto Y et al. A novel action of collapsin: collapsin-1 increases antereo- and retrograde axoplasmic transport independently of growth cone collapse J Neurobiol 1997; 33: 316–328

    Article  CAS  PubMed  Google Scholar 

  14. Wang L-H, Strittmatter SM . A family of rat CRMP genes is differentially expressed in the nervous system J Neurosci 1996; 16: 6197–6207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hamajima N, Matsuda K, Sakata S, Tamaki N, Sasaki M, Nonaka M . A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution Gene 1996; 180: 157–163

    Article  CAS  PubMed  Google Scholar 

  16. Putman CW, Rotteveel JJ, Wevers RA, van Gennip AH, Bakkeren JA, De Abreu RA . Dihydropyrimidinase deficiency, a progressive neurological disorder? Neuropediatrics 1997; 28: 106–110

    Article  CAS  PubMed  Google Scholar 

  17. Henderson MJ, Ward K, Simmonds HA, Duley JA, Davies PM . Dihydropyrimidinase deficiency presenting in infancy with severe developmental delay J Inherit Metab Dis 1993; 16: 574–576

    Article  CAS  PubMed  Google Scholar 

  18. Hayes SG . Azetazolamide in bipolar affective disorders Ann Clin Psych 1994; 6: 91–98

    Article  CAS  Google Scholar 

  19. Giacobni E . A cytochemical study of the localization of carbonic anhydrase in the nervous system J Neurochem 1962; 9: 169–177

    Article  Google Scholar 

  20. Roussel G, Delaunoy JP, Nussbaum JL, Mandel P . Demonstration of a specific localization of carbonic anhydrase C in the glial cells of rat CNS by an immunohistochemical method Brain Res 1979; 160: 47–55

    Article  CAS  PubMed  Google Scholar 

  21. Chesler M, Kaila K . Modulation of pH by neuronal activity TINS 1992; 15: 396–402

    CAS  PubMed  Google Scholar 

  22. Willson VJC, Graham JG, McQueen INF, Thompson RJ . Immunoreactive aldolase C in cerebrospinal fluid of patients with neurological disorders Ann Clin Biochem 1980; 17: 110–113

    Article  CAS  PubMed  Google Scholar 

  23. Meltzer H . Creative kinase and aldolase in serum: abnormality common to acute psychoses Science 1968; 159: 1368–1370

    Article  CAS  PubMed  Google Scholar 

  24. Meltzer H . Increased activity of creatine phosphokinase and aldolase activity in the acute psychoses: case report J Psychiat Res 1970; 7: 249–262

    Article  CAS  PubMed  Google Scholar 

  25. Coffey JW, Heath RG, Guschwan AF . Serum creatine kinase, aldolase, and copper in acute and chronic schizophrenics Biol Psych 1970; 2: 331–339

    CAS  Google Scholar 

  26. Meltzer HY, Grinspoon L, Shader RI . Serum creatine phophokinase and aldolase activity in acute schizophrenic patients and their relatives Compr Psychiatry 1970; 11: 552–558

    Article  CAS  PubMed  Google Scholar 

  27. Pol S, Bousquet-Lemercier B, Pave-Preux M, Pawlak A, Nalpas B, Berthelot P et al. Nucleotide sequence and tissue distribution of the human mitochondrial aspartate aminotransferase mRNA Biochem Biophys Res Commun 1988; 157: 1309–1315

    Article  CAS  PubMed  Google Scholar 

  28. Mulcrone J, Whatley SA, Ferrier IN, Marchbanks R . A study of altered gene expression in frontal cortex from schizophrenic patients using differential screening Schizophr Res 1995; 14: 203–213

    Article  CAS  PubMed  Google Scholar 

  29. Bigbee JW, Eng LF . Analysis and comparison of in vitro synthesized glial fibrillary acidic protein with rat CNS intermediate filament proteins J Neurochem 1982; 38: 130–134

    Article  CAS  PubMed  Google Scholar 

  30. Ishida K, Kaneko K, Kubota T, Itoh Y, Miyatake T, Matsushita M et al. Identification and characterization of an anti-glial fibrillary acidic protein antibody with a unique specificity in a demented patient with an autoimmune disorder J Neurol Sci 1997; 151: 41–48

    Article  CAS  PubMed  Google Scholar 

  31. Fujita K, Yamauchi M, Matsui T, Titani K, Takahashi H, Kato T et al. Increase of glial fibrillary acidic protein fragments in the spinal cord of motor neuron degeneration mutant mouse Brain Res 1998; 785: 31–40

    Article  CAS  PubMed  Google Scholar 

  32. Laping NJ, Nichols NR, Day JR, Johnson SA, Finch CE . Transcriptional control of glial fibrillary acidic protein and glutamine synthetase in vivo shows opposite responses to corticosterone in the hippocampus Endocrinology 1994; 135: 1928–1933

    Article  CAS  PubMed  Google Scholar 

  33. Norton WT, Aquino DA, Hozumi I, Chui F-C, Brosnan CF . Quantitative aspects of reactive gliosis: a review Neurochem Res 1992; 17: 877–885

    Article  CAS  PubMed  Google Scholar 

  34. Tardy M, Fages C, LePrince G, Rolland B, Nunez J . Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes Mol Aspects Dev Aging Nerv Syst 1990; 265: 41–52

    Article  CAS  Google Scholar 

  35. Inagaki M, Gonda Y, Nishizawa K, Kitamura S, Sato C, Ando S et al. Phosphorylation sites linked to glial filament disassembly in vitro locate in a non-alpha-helical head domain J Biol Chem 1990; 265: 4722–4729

    CAS  PubMed  Google Scholar 

  36. Inagaki M, Nakamura Y, Masatoshi T, Nishimura T, Inagaki N . Glial fibrillary acidic protein: dynamic property and regulation by phosphorylation Brain Pathol 1994; 4: 239–243

    Article  CAS  PubMed  Google Scholar 

  37. Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL . Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia Proc Natl Acad Sci USA 1996; 93: 14182–14187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eng L, Ghirnikar RS . GFAP and astrogliosis Brain Pathol 1994; 4: 229–237

    Article  CAS  PubMed  Google Scholar 

  39. Goodison KL, Parhad IM, White CL III, Sima AF, Clark AW . Neuronal and glial gene expression in neocortex of Down's Syndrome and Alzheimer's Disease J Neuropath Exp Neuro 1993; 52: 192–198

    Article  CAS  Google Scholar 

  40. Murphy GM Jr, Lee YL, Jia XC, Yu AC, Majewska A, Song Y et al. Tumor necrosis factor-α and basic fibroblast growth factor decrease glial fibrillary acidic protein and its encoding mRNA in astrocyte cultures and glioblastoma cells J Neurochem 1995; 65: 2716–2714

    Article  PubMed  Google Scholar 

  41. Rinaman L, Card JP, Enquist LW . Spatiotemporal responses of astrocytes, ramified microglia, and brain macrophages to central neuronal infection with pseudorabies virus J Neurosci 1993; 13: 687–700

    Article  Google Scholar 

  42. Kennedy PG, Ajor EO, Williams RK, Straus SE . Down-regulation of glial fibrillary acidic protein expression during acute lyticvaricella-zoster virus infection of cultured human astrocytes Virology 1994; 205: 558–562

    Article  CAS  PubMed  Google Scholar 

  43. Pulliam L, West D, Haigwood N, Swanson RA . HIV-1 envelope gp120 alters astrocytes in human brain cultures AIDS Res Hum Retroviruses 1993; 9: 439–444

    Article  CAS  PubMed  Google Scholar 

  44. Levi G, Patrizio M, Bernardo A, Petrucci TC, Agresti C . Human immunodeficiency virus coat protein gp120 inhibits the β-adrenergic regulation of astroglial and microglial functions Proc Natl Acad Sci USA 1993; 90: 1541–1545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the Stanley Foundation for funding this work. We would also like to thank Dr Maree Webster for her technical input, Dr Lydie Meheus of Innogenetics for sequencing and peptide IDs, and Ms Ann Cusic for the preparation of this manuscript.

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Correspondence to N L Johnston-Wilson.

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Johnston-Wilson, N., Sims, C., Hofmann, JP. et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psychiatry 5, 142–149 (2000). https://doi.org/10.1038/sj.mp.4000696

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