Compact myelin exists in the absence of basic protein in the shiverer mutant mouse

Abstract

The myelin sheath is a multilamellar membrane system which surrounds axons in vertebrates and provides the electrical insulation necessary for saltatory nerve impulse conduction. Myelin forms from its cell of origin as a flattened, membrane-bound cytoplasmic process which wraps spirally around the axon; a periodic compact array of membrane pairs is produced from the wrappings as the cytoplasmic contents are extruded, and the external surfaces of membranes become apposed^1,2. Neurological mutant mice which show myelin abnormalities are useful models for examining the formation, stability and breakdown of myelin. For example, the shiverer mouse carries an autosomal recessive mutation³ (shi)⁴ that results in severe myelin deficiency in the central nervous system (CNS)^5,6, apparently due to a defect in myelin formation^5,6. The small amount of myelin that does form in the CNS is generally not compacted at its cytoplasmic surfaces⁶, possibly due to the low level of basic protein in shiverer CNS tissue⁷. In the peripheral nervous system (PNS), in contrast, amounts of compact myelin seem to be normal⁶. The coarse tremor and convulsions that begin at about 2 weeks of age in the shiverer are presumably due to the severe CNS deficiency of myelin, as similar neurological signs are shown by other mutants with reduced CNS myelin⁸. Most studies on such mutants have concentrated on those regions of the nervous system which are grossly deficient in myelin^5–10. In the other regions myelin seems by light microscopy to be normal. At the ultrastructural and molecular level, however, this myelin sometimes shows abnormalities^11–14, and this has prompted us to examine intensively such myelin in several neurological mutants. For this we have used X-ray diffraction, electron microscopy and SDS-polyacrylamide gel electrophoresis (SDS-PAGE). We report here that, of the mutants we have examined so far, the shiverer mouse is unique in showing a striking alteration in myelin protein composition that does not significantly affect the gross morphology and lamellar organisation of the myelin sheath. Our results thus question the proposed role of basic proteins^15–19 in myelin as ‘structural cement’.