Multiple Sclerosis (MS) is the most common disease among young adults in which primary' pathologic changes occur in the central nervous system. It has been characterized as a disease of unknown cause, inadequate treatment, and unpredictable course. In the developing lesions of MS, myelin is destroyed, and therefore, many studies have focused on the mechanisms involved in the injury, phagocytosis and removal of myelin. However, little work has been done to investigate whether oligodendrocytes (OLs), the cells which produce the myelin membrane, also play a role in the pathogenesis of the disease. Immature OLs and reactive astrocytes are present, particularly at the plaque edge. We hypothesize that early in the evolution of the MS lesion, a molecule(s) is present which induces mature OLs to transform into reactive astrocytes after which the cells detach from their myelin sheaths. The molecule(s) which trigger(s) the OL/reactive astrocyte transformation is unknown, but a key factor may be the excessive binding of a ligand to surface markers on OLs and/or myelin that activates a myelin basic protein (MBP)-mediated signal transduction pathway. In this proposal, we use binding of an antibody to the myelin surface marker galactocerebroside (GalC) as a model system to test our hypothesis. Our preliminary data show that binding of anti-GalC antibody induces a second messenger regulated cascade of events mediated by MBP which results in the apparent loss of mature OLs markers and the appearance of astrocyte intermediate filaments in mature oligodendrocytes. Specific questions addressed in this proposal include: Are mature oligodendrocytes plastic, i.e., are they capable of transforming into reactive astrocytes? How does MBP mediate this process? Are the new reactive astrocytes a source of remyelinating cells? The experiments described in this proposal employ in vitro culture of glial cells and cell lines, in conjunction with histochemical, immunochemical, and biochemical techniques which include the use of DNA and antibody probes for glial-specific genes and protein. The knowledge gained through these studies should provide a rational basis for improving treatment of MS patients and for understanding the molecular basis regulating demyelination not only in MS but also other demyelinating conditions.
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