Molecular network of the comprehensive multiple sclerosis brain-lesion proteome

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 alpha 1, type I alpha 2, type VI alpha 2, type VI alpha 3, fibronectin 1, fibulin 2, laminin alpha 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. Multiple Sclerosis 2009; 15: 531-541. http://msj.sagepub.com