title: Antibody cross-linking of myelin oligodendrocyte glycoprotein leads to its rapid repartitioning into detergent-insoluble fractions, and altered protein phosphorylation and cell morphology.
abstract: Myelin oligodendrocyte glycoprotein (MOG) is, quantitatively, a relatively minor component of the myelin membrane. Nevertheless, peritoneal administration of MOG evokes potent cellular and humoral immunoreactivity, resulting in an experimental allergic encephalitis with immunopathology similar to multiple sclerosis. Moreover, antibodies against MOG cause myelin destruction in situ. Therefore, it appears that MOG-related demyelination is dependent on anti-MOG antibody, but the mechanism(s) by which it occurs is unclear. Of potential significance are observations that some proteins are selectively partitioned into specialized plasma membrane microdomains rich in glycosphingolipids and cholesterol ("lipid rafts"). In particular, during ligand or antibody cross-linking, various plasma membrane receptors undergo enhanced partitioning into rafts as an obligatory first step toward participation in early signal transduction events. In contrast to mature myelin, in oligodendrocytes (OLs) in culture MOG is not raft associated [Triton X-100 (TX-100) soluble, 4 degrees C]. However, in this study we show that antibody cross-linking (anti-MOG plus secondary antibody) of MOG on the surface of OLs results in the repartitioning of approximately 95% of MOG into the TX-100-insoluble fraction. This repartitioning of MOG is rapid (<or=1 min), antibody dose dependent, requires an intact cytoskeleton, leads to phosphorylation or dephosphorylation of tyrosine, serine, and threonine residues in specific proteins (e.g., beta-tubulin, Gbeta1-2), and invokes a rapid retraction of OL processes. After removal of the cross-linking antibodies, these events are reversed. We hypothesize that antibody-mediated repartitioning of MOG into TX-100-insoluble glycosphingolipid-cholesterol-rich microdomains initiates specific cellular signaling that could be related to initial steps of MOG-mediated demyelination.
authors.affiliation: Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030-3401, USA. Marta@up.uchc.edu
authors.forename: C B
authors.initials: CB
authors.lastname: Marta
authors.forename: C M
authors.initials: CM
authors.lastname: Taylor
authors.forename: T
authors.initials: T
authors.lastname: Coetzee
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Winkler
authors.forename: R
authors.initials: R
authors.lastname: Bansal
authors.forename: S E
authors.initials: SE
authors.lastname: Pfeiffer
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology; D003902:Detergents / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D021962:Membrane Microdomains / Q000737:chemistry; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D017830:Octoxynol / Q000737:chemistry; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry
chemical_list: D000906:Antibodies; D003432:Cross-Linking Reagents; D003902:Detergents; D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D014404:Tubulin; D017830:Octoxynol