Signaling Cascades Activated upon Antibody Cross-linking of Myelin Oligodendrocyte Glycoprotein

Abstract

Antibody-induced demyelination is an important component of pathology in multiple sclerosis. In particular, antibodies to myelin oligodendrocyte glycoprotein (MOG) are elevated in multiple sclerosis patients, and they have been implicated as mediators of demyelina-tion. We have shown previously that antibody cross-linking of MOG in oligodendrocytes results in the repar-titioning of MOG into glycosphingolipid-cholesterol membrane microdomains ("lipid rafts"), followed by changes in the phosphorylation of specific proteins, including dephosphorylation of-tubulin and the sub-unit of the trimeric G protein and culminating in rapid and dramatic morphological alterations. In order to further elucidate the mechanism of anti-MOG-mediated de-myelination, we have carried out a proteomic analysis to identify the set of proteins for which the phosphoryl-ation states or expression levels are altered upon anti-MOG treatment. We demonstrate that treatment of oli-godendrocytes with anti-MOG alone leads to an increase in calcium influx and activation of the MAPK/Akt pathways that is independent of MOG repartitioning. However , further cross-linking of anti-MOGMOG complexes with a secondary anti-IgG results in the lipid raft-dependent phosphorylation of specific proteins related to cellular stress response and cytoskeletal stability. Oli-godendrocyte survival is not compromised by these treatments. We discuss the possible significance of the anti-MOG-induced signaling cascade in relation to the initial steps of MOG-mediated demyelination.