Proteinases and demyelination

Our interest in proteolytic enzymes derives from our work on the pathogenesis of multiple sclerosis (MS). In this disease of the central nervous system the myelin sheaths enveloping the axons disintegrate, usually in a patchy manner beginning around small veins or near the ventricles, resulting in lesions or “plaques.” The cause of MS is still unknown. At present it is believed that a virus may be involved, possibly one which destroys the cells that produce and maintain the myelin, the oligodendrocytes. Alternatively, or as a result of the presence of such a virus (long sought, but still not identified), an autoimmune reaction against the oligodendrocytes or their myelin is invoked as the probable cause (24). The latter possibility has been intensively studied in analogy with what may be an animal model for MS. experimental allergic encephalomyelitis (EAE), which is a disease produced in experimental animals by immunological reactions to injections, in complete Freund’s adjuvant, of central nervous system (CNS) tissue, myelin, or myelin basic protein (13). Whether EAE is a relevant model for MS is a matter of some controversy. Whatever the cause of MS may be, it is important to elucidate the pathogenesis of myelin breakdown; if an enzyme is responsible, there beckons the possibility of halting the inexorable progression ofthe disease by administering enzyme inhibitors. More than ten years ago it was proposed that a proteolytic attack on the basic protein ofmye!in (which is very vulnerable to proteolysis) might be the initial step of myelin dissolution. Hallpike and Adams (7) demonstrated that myelin basic protein disappears from the edge of MS plaques; a gelatin film technique showed increased acid proteinase activity in and around such plaques. Einstein et a!. (6) found that brain