Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes

Nellie A. Martin, Arkadiusz Nawrocki, Viktor Molnar, Maria L. Elkjaer, Eva K. Thygesen, Miklos Palkovits, Peter Acs, Tobias Sejbaek, Helle H. Nielsen, Zoltan Hegedus, Finn Sellebjerg, Tihamer Molnar, Eudes G.V. Barbosa, Nicolas Alcaraz, Ferenc Gallyas, Asa F. Svenningsen, Jan Baumbach, Hans Lassmann, Martin R. Larsen, Zsolt Illes

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Objective Here, we applied a multi-omics approach (i) to examine molecular pathways related to de- and remyelination in multiple sclerosis (MS) lesions; and (ii) to translate these findings to the CSF proteome in order to identify molecules that are differentially expressed among MS subtypes. Methods To relate differentially expressed genes in MS lesions to de- and remyelination, we compared transcriptome of MS lesions to transcriptome of cuprizone (CPZ)-induced de- and remyelination. Protein products of the overlapping orthologous genes were measured within the CSF by quantitative proteomics, parallel reaction monitoring (PRM). Differentially regulated proteins were correlated with molecular markers of inflammation by using MesoScale multiplex immunoassay. Expression kinetics of differentially regulated orthologous genes and proteins were examined in the CPZ model. Results In the demyelinated and remyelinated corpus callosum, we detected 1239 differentially expressed genes; 91 orthologues were also differentially expressed in MS lesions. Pathway analysis of these orthologues suggested that the TYROBP (DAP12)-TREM2 pathway, TNF-receptor 1, CYBA and the proteasome subunit PSMB9 were related to de- and remyelination. We designed 129 peptides representing 51 orthologous proteins, measured them by PRM in 97 individual CSF, and compared their levels between relapsing (n = 40) and progressive MS (n = 57). Four proteins were differentially regulated among relapsing and progressive MS: tyrosine protein kinase receptor UFO (UFO), TIMP-1, apolipoprotein C-II (APOC2), and beta-2-microglobulin (B2M). The orthologous genes/proteins in the mouse brain peaked during acute remyelination. UFO, TIMP-1 and B2M levels correlated inversely with inflammation in the CSF (IL-6, MCP-1/CCL2, TARC/CCL17). APOC2 showed positive correlation with IL-2, IL-16 and eotaxin-3/CCL26. Conclusions Pathology-based multi-omics identified four CSF markers that were differentially expressed in MS subtypes. Upregulated TIMP-1, UFO and B2M orthologues in relapsing MS were associated with reduced inflammation and reflected reparatory processes, in contrast to the upregulated orthologue APOC2 in progressive MS that reflected changes in lipid metabolism associated with increased inflammation.

Original languageEnglish
Article numbere0202530
JournalPloS one
Issue number8
Publication statusPublished - Aug 2018


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Martin, N. A., Nawrocki, A., Molnar, V., Elkjaer, M. L., Thygesen, E. K., Palkovits, M., Acs, P., Sejbaek, T., Nielsen, H. H., Hegedus, Z., Sellebjerg, F., Molnar, T., Barbosa, E. G. V., Alcaraz, N., Gallyas, F., Svenningsen, A. F., Baumbach, J., Lassmann, H., Larsen, M. R., & Illes, Z. (2018). Orthologous proteins of experimental de- and remyelination are differentially regulated in the CSF proteome of multiple sclerosis subtypes. PloS one, 13(8), [e0202530]. https://doi.org/10.1371/journal.pone.0202530