Marta Cecilia B, Montano Michael B, Taylor Christopher M, Taylor Ava L, Bansal Rashmi, Pfeiffer Steven E
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030-3401, USA.
J Biol Chem. 2005 Mar 11;280(10):8985-93. doi: 10.1074/jbc.M413174200. Epub 2005 Jan 4.
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.
抗体诱导的脱髓鞘是多发性硬化症病理学的一个重要组成部分。特别是，髓鞘少突胶质细胞糖蛋白（MOG）抗体在多发性硬化症患者中升高，并且它们被认为是脱髓鞘的介质。我们之前已经表明，少突胶质细胞中MOG的抗体交联导致MOG重新分配到糖鞘脂 - 胆固醇膜微区（“脂筏”）中，随后特定蛋白质的磷酸化发生变化，包括β-微管蛋白和三聚体G蛋白的β亚基去磷酸化，并最终导致快速而显著的形态学改变。为了进一步阐明抗MOG介导的脱髓鞘机制，我们进行了蛋白质组学分析，以鉴定抗MOG处理后磷酸化状态或表达水平发生改变的蛋白质组。我们证明，单独用抗MOG处理少突胶质细胞会导致钙内流增加和MAPK/Akt途径激活，这与MOG重新分配无关。然而，用二级抗IgG进一步交联抗MOG.MOG复合物会导致与细胞应激反应和细胞骨架稳定性相关的特定蛋白质的脂筏依赖性磷酸化。这些处理不会损害少突胶质细胞的存活。我们讨论了抗MOG诱导的信号级联反应与MOG介导的脱髓鞘初始步骤相关的可能意义。
