Signaling cascades activated upon antibody cross-linking of myelin oligodendrocyte glycoprotein: potential implications for multiple sclerosis.
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 demyelination. We have shown previously that antibody cross-linking of MOG in oligodendrocytes results in the repartitioning of MOG into glycosphingolipid-cholesterol membrane microdomains ("lipid rafts"), followed by changes in the phosphorylation of specific proteins, including dephosphorylation of beta-tubulin and the beta subunit of the trimeric G protein and culminating in rapid and dramatic morphological alterations. In order to further elucidate the mechanism of anti-MOG-mediated demyelination, we have carried out a proteomic analysis to identify the set of proteins for which the phosphorylation states or expression levels are altered upon anti-MOG treatment. We demonstrate that treatment of oligodendrocytes 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-MOG.MOG complexes with a secondary anti-IgG results in the lipid raft-dependent phosphorylation of specific proteins related to cellular stress response and cytoskeletal stability. Oligodendrocyte 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.
Marta
Cecilia B
CB
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030-3401, USA. Marta@up.uchc.edu
Montano
Michael B
MB
Taylor
Christopher M
CM
Taylor
Ava L
AL
Bansal
Rashmi
R
Pfeiffer
Steven E
SE
D000818:Animals; D000906:Antibodies / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000503:physiopathology; D007074:Immunoglobulin G; D021962:Membrane Microdomains / Q000276:immunology / Q000502:physiology; D051379:Mice; D009103:Multiple Sclerosis / Q000503:physiopathology*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology* / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D010766:Phosphorylation; D020543:Proteome; D015398:Signal Transduction / Q000502:physiology*
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D020543:Proteome