The myelin sheath of the central nervous system is a compositionally and structurally modified extension of the surface membrane of the oligodendroglial cell. It contains unique proteins, including proteolipid protein (PLP), which accounts for over one-third of myelin protein, and unique lipids, including galactosylceramide (cerebroside), which accounts for a quarter of myelin lipid. This specialized composition results in a characteristic ultrastructure of a spiral of compacted membranes. The myelin sheath also is less fluid and has slower metabolic turnover than most other membranes. There are now available """"""""knockout"""""""" mutant mice which lack functional genes for the expression of PLP or cerebroside. Surprisingly, these animals still accumulate a significant amount of myelin and survive for several months (cerebroside knockout) or have an almost normal life-span (PLP knockout). We postulate that the compositional abnormalities are compensated for by metabolic plasticity, to a significant degree for the CGT knockout and almost completely for the PLP knockout. Specifically, we will test the hypothesis that the myelin in these mutants is unstable and degraded more rapidly than in controls, but that this is compensated for by a considerably enhanced rate of synthesis of myelin components. We suggest that the same holds true when there is a toxicant-induced insult that destabilizes myelin - there is compensation by upregulation of synthesis of myelin components. The model for this will be triethyltin-induced edema. We will also investigate whether toxicant-induced insult and genetic factors interact in causing metabolic instability of myelin. The specific experiments proposed involve injection of radioactive precursors into mice and monitoring the extent of synthesis of lipids and their incorporation into myelin, and then their subsequent metabolic turnover. We expect the results will lead to better understanding of the pathophysiology of myelin disorders, and give insight into the basis of metabolic resistance to toxicant-induced destabilization of myelin. This should also lead to a more sensitive assay for genetic or environmental perturbations which may result in myelin damage.
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