It has long been known that some constituents of the myelin sheaths of the central nervous system are metabolically stable (a half-life on the order of months or longer), while the more rapidly turning over constituents have a half-life on the order of days. Recently, we demonstrated that at least one constituent of the myelin sheath, the phosphate group which modifies basic proteins, turns over with a half-life on the order of minutes. Since very rapid turnover of a molecule is often related to functional significance, we have developed a research strategy to search for other very rapidly turning over components of the myelin sheath. We will also attempt to define any sub-myelin compartment (myelin sub-fraction) which may preferentially contain rapidly turning over myelin components. Knowledge of the type of components which turn over rapidly, and of their location, should serve as a clue as to the function of these molecules. Another probe of the dynamics of myelin membrane structure has to do with how rapidly the steroid components of myelin become available for exchange with cholestrol in other metabolic compartments. A research strategy involving treatment of young rats with hypercholesterolemic agents will be used to accumulate cholestrol precursors in the deveoping myelin membrane (7-dehydrocholesterol and desmosterol can replace much of normally appearing cholesterol). After termination of treatment the time course of the exchange of the cholesterol precursors with cholesterol in other membranes will be determined. Another area of myelin metabolism to be investigated is the role of the several possible pathways for biosynthesis of phosphatidylethanolamine. This lipid can be formed by decarboxylation of phosphatidylserine, by an exchange reaction in which ethanolamine replaces a pre-existing base moiety, or by a CDP-ethanolamine dependent synthesis. We will attempt to assess the contributions of these pathways to the synthesis of phosthatidylethanolamine of myelin (i.e. is one of these pathways preferentially represented in myelin forming cells?). The goal of the study is to gain an understanding of mechanisms involved in the formation and maintenance of the myelin sheath so that it can be better understood how specific pathological events can impair the formation of myelin or bring about degradation of formed myelin.
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