Characterization of a neural proteinase which may play a key role in demyelinating disease.

Compaction at the cytoplasmic apposition of multilammellar myelin sheaths in the central nervous system (CNS) is facilitated by an extrinsic membrane polypeptide, myelin basic protein (MBP). MBP has long been a focus of attention in studies on multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). MBP levels are reduced in white matter from MS and EAE tissue, and MBP fragments in spinal fluid samples may be diagnostic for ongoing demyelination (Whitaker, 1984). In addition, MBP is a potent inducer of EAE in many species (Kies, 1985). Extracellular disintegration of myelin sheaths has been observed by electron microscopy of EAE CNS tissue. At the edge of dissolving compact myelin, each lamella often has a small membranous loop, arising from a split at the cytoplasmic apposition (Lampert, 1983). This observation raises the possibility that proteinases acting within the myelin sheath itself could degrade MBP and contribute to this pattern of myelinolysis. Myelin membranes can be isolated, with little contamination from other neural organelles, by density gradient centrifugation. MBP is labile when myelin membranes are incubated at physiological ionic strength because of neutral protease activities in the preparations (Sato et a/., 1982). Recently we have examined MBP interactions with isolated myelin membranes in some detail (Glynn et ul., 1987; Chantry et a/., 1988; Earl et al., 1988). The critical first step in the degradation of MBP in this system is its dissociation