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 (+9 others)
2018 PLoS ONE  
Objective Here, we applied a multi-omics approach (i) to examine molecular pathways related to deand 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. OPEN ACCESS Citation: Martin NA, Nawrocki A, Molnar V, Elkjaer ML, Thygesen EK, Palkovits M, et al. (2018) Orthologous proteins of experimental de-and remyelination are differentially regulated in the CSF
more » ... teome of multiple sclerosis subtypes. PLoS ONE 13(8): e0202530. https://doi.org/10. 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.
doi:10.1371/journal.pone.0202530 pmid:30114292 fatcat:wks4lbhhjzfb7hzibfpb7pkxtu