GLYCOPROTEINS AND GLYCOLIPIDS ASSOCIATED WITH MYELIN IN DEVELOPMENT AND DISEASE

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This project focuses on glycoconjugates of Schwann cells and oligodendrocytes during myelination and demyelination. A major aspect of the research concerns the myelin-associated glycoprotein (MAG), which is localized in periaxonal glial membranes of myelinated fibers and functions in transmitting signals between axons and myelin-forming cells. MAG is in the "siglec" subgroup of the immunoglobulin superfamily and binds to glycoconjugates containing terminal alpha2-3-linked sialic acid. This suggests that its axonal receptor or ligand could be a glycoprotein or ganglioside, and that sialic acid moieties on other glycoconjugates 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 inherited mouse and human neuropathies, and our results suggest that this contributes to pathology by interfering with the normal functioning of MAG. Also, we obtained evidence indicating that some microtubule-associated protein 1B (MAP1B) is expressed as a sialylated membrane glycoprotein on the axonal surface and interacts with MAG. If MAP1B is a physiological binding partner for MAG, it could function in the transmission of MAG-mediated signals that are known to affect the cytoskeletal structure of myelinated axons (see below). MAG knockout mice myelinate relatively normally during early development, but neuropathological changes occur as the mice age. Myelinated axons in the peripheral nervous system degenerate in association with a reduction of axonal caliber caused by cytoskeletal abnormalities, including decreased expression and phosphorylation of neurofilaments. These observations suggest that MAG participates in a signaling pathway from Schwann cells to myelinated axons that is essential for integrity of the axonal cytoskeleton. We have shown that the decreased phosphorylation of neurofilaments in MAG-null mice is due in part to decreased activities of extracellular signal regulated kinases (ERKs) and cyclin dependent kinase 5 (cdk5). Furthermore, the effects of MAG-mediated signaling on the expression and phosphorylation of cytoskeletal elements can be demonstrated in vitro in neurons co-cultured with MAG-expressing cells or treated with a MAG-Fc chimera. These in vitro models provide a means for further investigation of the mechanism of MAG-mediated signaling by pharmacological approaches. Biochemical analyses of the brains of aging MAG-knockout mice demonstrated normal levels of the proteins of compact myelin (myelin basic protein and proteolipid protein), but decreased levels of oligodendroglial proteins such as 2',3'-cyclic nucleotide 3'-phosphodiesterase and the 120 kD isoform of neural cell adhesion molecule. These findings are indicative of oligodendroglial pathology and consistent with the morphological demonstration of a "dying back" oligodendrogliopathy in aging MAG-null mice. Our previous research on multiple sclerosis (MS) had shown that, in comparison to other myelin proteins, MAG is preferentially lost from the edge of some active MS plaques. Because MAG is localized exclusively in periaxonal membranes of oligodendroctyes in adult brain, its selective loss in MS suggests that there is damage to these distal oligodendroglial membranes. This was interpreted to be due to a dying back oligodendrogliopathy in MS, and the occurrence of a similar oligodendrogliopathy in MAG-null mice suggests that the loss of MAG in MS is not just a marker for damage to periaxonal membranes, but may actively contribute to this pathology.