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Proteome Analysis ofSchizophrenia Brain Tissue
Max Planck Institute for PsychiatryProteomics and Biomarkers
München - Germany
Laboratory of Neuroscience (LIM-27)Dept of Psychiatry, Faculty of Medicine
University of São Paulo, Brazil
Laboratory of ProteomicsDept of Biochemistry, State University of Campinas,
Brazil
Daniel Martins-de-Souza
Proteome of Schizophrenia
Schizophrenia(SCZ)
* Chronic and debilitating psychotic disorder
* Affects about 1% of world population
* Multifactorial disease caused by differential gene and protein expression + environmental factors
Proteome of Schizophrenia
Proteome of Schizophrenia
Genomics
Knowledge of the complete set of genesto reveal the diseases mechanisms
Proteome of Schizophrenia
Why Proteomics?
Proteome of Schizophrenia
Post-Genome:
Post-Genome EraA comprehensive set of unknown genes and products
Proteome of Schizophrenia
Proteomics
The set of expressed proteins ofa cell, tissue or organism.
„The real players“
Proteome of Schizophrenia
Proteome of SchizophreniaProteome of Schizophrenia
Mass Spectrometry MALDI-TOF
Two-Dimensional Gel Electrophoresis (2DE) andMass Spectrometry (MS)
Proteome of Schizophrenia
Shotgun Mass SpectrometryProteome of Schizophrenia
Martins-de-Souza et al.J Neural Transm. 2008
Proteome of Schizophrenia
Schizophrenia and Proteomics
Our goals
* Molecular markers for diagnosis
* Pathobiology of the disease
Proteome of Schizophrenia
Proteome of Schizophrenia
Investigated Brain RegionsProvided by BrainNet Europe
Proteome of Schizophrenia
http://www.nih.gov/news/research_matters/november2007/11192007brain.htm
Dorsolateral Prefrontal Cortex(BA46)
Shotgun-MS and 2DE/MS
Anterior Temporal Lobe(BA38)
Shotgun-MS
Wernicke’s Area(BA22p)2DE/MS
Confirm differentiallyexpressed genes and proteins
Novel differentially expressed proteins
Proteome of Schizophrenia
Dorsolateral Prefrontal Cortex
2DE/MS: 14 upregulated and 10 downregulated proteins
Shotgun/MS: 77 upregulated and 7 downregulated proteins
Proteome of Schizophrenia
Proteome of Schizophrenia
Dorsolateral Prefrontal Cortex2DE/MS and Shotgun-MS
Proteome of Schizophrenia
a) Energy Metabolism
b) Oxidative stress
c) Oligodendrocytesmetabolism
d) Calcium homeostasis
e) Immune System-related
f) Cytoskeleton
Martins-de-Souza et al.J Psychiatr Res. 2008
in press
Martins-de-Souza et al.Eur Arch Psychiatry Clin Neurosci. 2008 - in press
Proteome of Schizophrenia
Anterior Temporal LobeShotgun-MS
Proteome of Schizophrenia
6 upregulated and 31 downregulated proteins
a) Oligodendrocytes metabolism
b) Calcium homeostasis
c) Cytoskeleton
Proteome of Schizophrenia
Wernicke’s Area2DE/MS
Proteome of Schizophrenia
14 upregulated and11 downregulated proteins
a) Energy Metabolism
b) Cytoskeleton
Martins-de-Souza et al.BMC Psychiatry 2008
submitted
Proteome of Schizophrenia
SCZ Differential ProteomeOur results:
Proteome of Schizophrenia
15 different biological processes
19 proteins commonlyregulated in the 3 regions
of the same patients
10 same direction
9 different direction
Proteome of Schizophrenia
SCZ Differential ProteomeProteome of Schizophrenia
Biological Processes Revealed in SCZ
Metabolism; Energy pathways
23%
Cell Growth and/or maintenance
18%
Signal transduction and Cell communication
17%
Protein Metabolism9%
Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism.
7%
Unknown Biological Process
6%
Transport5%
Oligodendrocyte Metabolism
3%
Immune Response4%
Regulation of gene expression
1%
DNA repair1%
Osmoregulation/Hormone metabolism
1%Nucleic acid metabolism
1%
Synaptic Transmission2%
Neurogenesis2%
15 different biological processes
Proteome of Schizophrenia
SCZ Differential ProteomeProteome of Schizophrenia
Calcium Differential Influx, Immune System and Neurotransmission
Dopamine receptorsare Ca+2
dependent
Glutaminevesicles proteins
Immune System-related
HSPs and antibodies
Jones et al.Immunol Cell Biol.
2005 Feb;83(1):9-17.
Proteome of Schizophrenia
SCZ Differential ProteomeProteome of Schizophrenia
Oligodendrocyte Metabolism
MBP & MOG & Ermindownregulated
http://neurophilosophy.files.wordpress.com
2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP)
http://stemcells.nih.gov/StaticResources/info/scireport/images/figure81.jpg
Proteome of Schizophrenia
Biomarker CandidatesProteome of Schizophrenia
Martins-de-Souza et al.BMC Psychiatry 2008
submitted
Proteome of Schizophrenia
DOPAMINERGIC dysfunctionDOPAMINERGIC dysfunction
IMMUNEresponse
SCZ Pathobiology
Genetic differences(small effects)
NEURODEVELOPMENT(Morphologic alterations)
DIFFERENTIAL GENE AND PROTEIN EXPRESSION
ENVIROMENTAL FACTOR(exogen alteration)
GLUTAMATERGIC dysfunction SEROTONERGIC dysfunction
Altered state ofNMDA receptors
Differential Ca+2 flow
ApoptosisROSNONeuronal Transmission
Cellular Death?
Neuronal and Synaptic Plasticity
MITOCHONDRIALdysfunction
Myelination systematically altered
Differential Ca+2 flow
MITOCHONDRIALdysfunction
IMMUNEresponse Myelination systematically altered
GLUTAMATERGIC dysfunction
Neuronal Transmission
Neuronal and Synaptic Plasticity
Proteome of Schizophrenia
Next Steps:
* Proteome of different brain regions(Proteome of complete SCZ brain – clinical aspects)
* Validate the common biomarker candidatesin brain tissue, CSF and plasma/serum
* Investigation of protein biomarkersin vivo and in vitro
* Proteome analysis of naive patient specimens(Prabakaran et al., 2007)
Proteome of Schizophrenia
Max Planck Institute for Psychiatry
München – Germany
Prof. Dr. Chris W. TurckDr. Giuseppina Maccarrone
Christiane Rewerts Maria Lebar
Dr. Jeeva VaradarajuluLarysa TeplytskaStefan Reckow
Philipp GormannsChristian Webhofer
Yaoyang ZhangMichaela Filiou
Dr. Claudia DitzenProf. Dr. Florian Holsboer
Laboratory of Neuroscience LIM-27
University of São Paulo, Brazil
Dr. Emmanuel Dias-NetoProf. Dr. Wagner F. Gattaz
Laboratory of ProteomicsState University of Campinas,
Brazil
Prof. Dr. José Camillo NovelloProf. Dr. Sérgio Marangoni
Georg-August-Universität Göttingen
Dept of Neuropathology
Dr. Andrea SchmittProf. Dr. Peter Falkai
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