Proteome Analysis of Schizophrenia Brain Tissue · Martins-de-Souza et al. J Psychiatr Res. 2008 in...

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



Genomics

Knowledge of the complete set of genesto reveal the diseases mechanisms


Why Proteomics?


Pre-Genome:

Pre-Genome EraA small set of well known genes


Post-Genome:

Post-Genome EraA comprehensive set of unknown genes and products


Same Genome, Different Proteome

MuscleNeuron

Neutrofile


Proteomics

The set of expressed proteins ofa cell, tissue or organism.

„The real players“


Proteome of SchizophreniaProteome of Schizophrenia

Mass Spectrometry MALDI-TOF

Two-Dimensional Gel Electrophoresis (2DE) andMass Spectrometry (MS)

Proteome of SchizophreniaProteome of Schizophrenia

Two-Dimensional Gel Electrophoresis (2DE)


Shotgun Mass SpectrometryProteome of Schizophrenia

Martins-de-Souza et al.J Neural Transm. 2008


Schizophrenia and Proteomics

Our goals

* Molecular markers for diagnosis

* Pathobiology of the disease



Investigated Brain RegionsProvided by BrainNet Europe


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


Dorsolateral Prefrontal Cortex

2DE/MS: 14 upregulated and 10 downregulated proteins

Shotgun/MS: 77 upregulated and 7 downregulated proteins



Dorsolateral Prefrontal Cortex2DE/MS and Shotgun-MS


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


Anterior Temporal LobeShotgun-MS


6 upregulated and 31 downregulated proteins

a) Oligodendrocytes metabolism

b) Calcium homeostasis

c) Cytoskeleton


Wernicke’s Area2DE/MS


14 upregulated and11 downregulated proteins

a) Energy Metabolism

b) Cytoskeleton

Martins-de-Souza et al.BMC Psychiatry 2008

submitted


SCZ Differential ProteomeOur results:


15 different biological processes

19 proteins commonlyregulated in the 3 regions

of the same patients

10 same direction

9 different direction


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



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.



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


Biomarker CandidatesProteome of Schizophrenia

Martins-de-Souza et al.BMC Psychiatry 2008

submitted


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


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)


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


“The Scream”Edvard Munch(1863-1944)


Proteome Analysis of Schizophrenia Brain Tissue · Martins-de-Souza et al. J Psychiatr Res. 2008 in...

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