Molecular Network Analysis of Multiple Sclerosis Brain Lesion Proteome

Abstract

A recent proteomics study of multiple sclerosis (MS) brain lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination (Han MH et al. Nature 451 : 1076-1081, 2008). However, among thousands of proteins identified, nearly all of remaining proteins were left behind to be characterized in terms of their implications in MS brain lesion development. 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 plaque (AP), chronic active plaque (CAP), and chronic plaque (CP). The database search on KEGG and PANTHER indicated the relevance of extracellular matrix (ECM)-mediated focal adhesion and integrin signaling to CAP and CP proteome. IPA identified the network constructed with a wide range of ECM components as one of the networks highly relevant to CAP 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. 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 observations indicate that the selective blockade of the interaction between ECM and integrins would be a rational approach for designing inhibitors of chronic inflammatory demyelination in MS brain lesions.