GLYCOPROTEINS AND GLYCOLIPIDS ASSOCIATED WITH MYELIN IN DEVELOPMENT AND DISEASE

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This project focuses on glycoproteins and glycolipids of Schwann cells and oligodendrocytes during myelination and demyelination. A major aspect of the research concerns the myelin-associated glycoprotein (MAG) that is localized in periaxonal glial membranes of myelinated fibers and functions in transmitting signals between axons and myelin- forming cells. MAG is in the I-type lectin subgroup of the immunoglobulin superfamily and binds to glycoconjugates containing terminal alpha2-3 sialic acid, suggesting that its ligand could be a glycoprotein and that sialic acid moieties on other glycoproteins and on MAG itself could modulate its function. Whereas most of the sialic acid linkages on brain glycoproteins are well known to be alpha 2-3, we have found that sialic acid linkages in mouse and human peripheral nerve are predominantly alpha 2-6 Furthermore, the expression of alpha 2-3 sialic acid on MAG and other glycoproteins of nerve is increased in some animal and human neuropathies, and our results suggest that this contributes to pathology by interfering with MAG-mediated signaling. We have continued to investigate the finding reported last year that MAG binds to microtubule-associated protein 1B (MAP1B) and the surprising results suggesting some MAP1B in neurons is expressed as a sialylated surface membrane glycoprotein. If MAP1B is a physiological ligand for MAG, it could function in the transmission of MAG-mediated signals that are known to affect the cytoskeletal structure of myelinated axons. A detailed biochemical investigation of MAG knockout mice and experiments with cocultures of MAG-expressing cells and neurons are underway to further define the molecular mechanisms involved in MAG function. The previous project reports entitled Disorders of CNS Myelin(Z01 NS 02848 LMCN) and Antibodies to Glycoconjugates in Neurological Diseases (Z01 NS 02786 LMCN) describing our clinically-related research on myelin have been terminated, and results in those areas will be incorporated into this project beginning this year. Our previous research on multiple sclerosis (MS) had shown that MAG is converted to a soluble 90 kD derivative (dMAG) by a cathepsin L-like neutral protease associated with myelin and is preferentially lost from the edge of active MS plaques in comparison to other myelin proteins. Since in adult brain, MAG is localized exclusively in periaxonal membranes of myelinating oligodendroctyes, the selective qualitative and quantitative alterations of MAG in MS indicate that there is damage to the periaxonal membranes, suggesting that one aspect of the pathology may be a dying-back oligodendrogliopathy. Experiments are being undertaken in MS tissue to determine what other periaxonal abnormalities occur in this disease and to compare the results to periaxonal changes in MAG knockout mice that also exhibit a dying-back oligodendrogliopathy. MAG has also been implicated in autoimmune demyelinating peripheral neuropathies in which anti-MAG IgM monoclonal antibodies are directed toward carbohydrate epitopes in MAG and cross react with other glycoproteins of PNS myelin including PO and PMP-22, as well as with the glycosphingolipid, sulfate-3-glucuronyl paragloboside (SGPG). However, our recent results have shown that these human antibodies exhibit substantial heterogeneity among patients with regard to the relative strengths with which they bind to these potential target antigens that could affect pathogenic mechanisms and contribute to clinical variability. - autoimmunity, ganglioside, glycolipid, glycoprotein, multiple sclerosis, myelin, neuropathy, oligodendrocyte, Schwann cell