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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
O'Farrell P . High resolution two-dimensional electrophoresis of proteins J Biol Chem 1975; 250: 4007–4021
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
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
Harrington M, Merril CR, Torrey EF . Differences in cerebrospinal fluid proteins between patients with schizophrenia and normal persons Clin Chem 1985; 31: 722–726
Merril CR, Harrington MG . Use of two-dimensional electrophoretic protein maps in studies of schizophrenia Schizophr Bull 1988; 14: 249–254
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
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
James P . Of genomes and proteomes Biochem Biophys Res Commun 1997; 231: 1–6
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
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
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
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
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
Wang L-H, Strittmatter SM . A family of rat CRMP genes is differentially expressed in the nervous system J Neurosci 1996; 16: 6197–6207
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
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
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
Hayes SG . Azetazolamide in bipolar affective disorders Ann Clin Psych 1994; 6: 91–98
Giacobni E . A cytochemical study of the localization of carbonic anhydrase in the nervous system J Neurochem 1962; 9: 169–177
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
Chesler M, Kaila K . Modulation of pH by neuronal activity TINS 1992; 15: 396–402
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
Meltzer H . Creative kinase and aldolase in serum: abnormality common to acute psychoses Science 1968; 159: 1368–1370
Meltzer H . Increased activity of creatine phosphokinase and aldolase activity in the acute psychoses: case report J Psychiat Res 1970; 7: 249–262
Coffey JW, Heath RG, Guschwan AF . Serum creatine kinase, aldolase, and copper in acute and chronic schizophrenics Biol Psych 1970; 2: 331–339
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
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
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
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
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
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
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
Norton WT, Aquino DA, Hozumi I, Chui F-C, Brosnan CF . Quantitative aspects of reactive gliosis: a review Neurochem Res 1992; 17: 877–885
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
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
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
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
Eng L, Ghirnikar RS . GFAP and astrogliosis Brain Pathol 1994; 4: 229–237
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
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
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
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
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
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
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.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000696
Keywords
This article is cited by
-
Upregulation of carbonic anhydrase 1 beneficial for depressive disorder
Acta Neuropathologica Communications (2023)
-
DPYSL2/CRMP2 isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders
Molecular Psychiatry (2023)
-
Upregulation of S100A8 in peripheral blood mononuclear cells from patients with depression treated with SSRIs: a pilot study
Proteome Science (2023)
-
Altered levels of interleukins and neurotrophic growth factors in mood disorders and suicidality: an analysis from periphery to central nervous system
Translational Psychiatry (2021)
-
Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model
Archives of Toxicology (2021)