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Abstract

Proteolipid protein (PLP) is the primary protein component of CNS myelin, yet myelin from the PLPnull mouse has only minor ultrastructural abnormalities. Might compensation for a potentially unstable structure involve increased myelin synthesis and turnover? This was not the case; neither accumulation nor in vivo synthesis rates for the myelin- specific lipid cerebroside was altered in PLPnull mice relative to wild-type (wt) animals. However, the yield of myelin from PLPnull mice, assayed as levels of cerebroside, was only about 55% of wt control levels. Loss of myelin occurred during initial centrifugation of brain homogenate at 20,000g for 20 min, which is sufficient to sediment almost all myelin from wt mice. Cerebroside-containing fragments from PLPnull mice remaining in the supernatant could be sedimented by more stringent centrifugation, 100,000g for 60 min. Both the rapidly. and the more slowly sedimenting cerebroside-containing membranes banded at the 0.85/0.32 M sucrose interface of a density gradient, as did myelin from wt mice. These results suggest at least some myelin from PLPnull mice differs from wt myelin with respect to physical stability (fragmented into smaller particles during dispersion) and/or density. Alternatively, slowly sedimenting cerebroside-containing particles could be myelin precursor membranes that, lacking PLP, were retarded in their processing toward mature myelin and thus differ from mature myelin in physical properties. If this is so, recently synthesized cerebroside should be preferentially found in these "slower-sedimenting" myelin precursor fragments. Metabolic tracer experiments showed this was not the case. We conclude that PLPnull myelin is physically less stable and/or less dense than wt myelin. (C) 2003 Wiley- Liss, Inc.