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Molecular network of the comprehensive multiple sclerosis brain-lesion proteome

Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan; Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan satoj{at}my-pharm.ac.jp

H Tabunoki

Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan

T Yamamura

Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan

Background

A recent proteomics study of multiple sclerosis (MS) lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination. However, among thousands of proteins examined, nearly all of remaining proteins are yet to be characterized in terms of their implications in MS brain-lesion development.

Methods

By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaques, chronic active plaques (CAP), and chronic plaques (CP).

Results

The database search on Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER) indicated the relevance of extracellular matrix (ECM)–mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain-lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Ingenuity pathway analysis (IPA) identified the network constructed with a wide range of ECM components, such as collagen, type I 1, type I 2, type VI 2, type VI 3, fibronectin 1, fibulin 2, laminin 1, vitronectin, and heparan sulfate proteoglycan, as one of the networks highly relevant to CAP proteome.

Conclusions

Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These in silico observations indicate that the selective blockade of the interaction between ECM and integrins in brain lesions in situ would be a target for therapeutic intervention in MS.

Key Words: extracellular matrix • multiple sclerosis • pathway analysis • proteome • systems biology

Multiple Sclerosis, Vol. 15, No. 5, 531-541 (2009)
DOI: 10.1177/1352458508101943


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