Myelin basic protein (MBP) and proteolipid protein (PLP) are major proteins of compact CNS myelin, whereas myelin-associated glycoprotein (MAG) and 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNP) are mainly localized in associated oligodendroglial membranes. These four myelin proteins are differently affected in various dysmyelinating, demyelinating and remyelinating circumstances, and information about changes in these proteins can increase our understanding of the specific molecular processes going on in each individual disease. In multiple sclerosis (MS), there is a preferential loss of MAG at the edges of the plaques. Although there is weak cellular and humoral immunity to MAG in MS, it seems unlikely that this is the cause of the preferential loss of MAG. Much of the MAG remaining in MS tissue is in the form of dMAG, a proteolytic cleavage product apparently formed from its breakdown by a myelin-associated, calcium-activated neutral protease. The MAG loss in MS may be related to this protease. Experiments in which myelin purified from different species was incubated at 37 degrees C. in a neutral buffer demonstrated that the rate of dMAG formation was greatest in human myelin, rapid in myelin from other primates, and substantially slower in myelin from lower mammals such as rodents. This suggests that dMAG formation may be especially relevant to human diseases. Although there are active attempts at remyelination in MS, the newly formed myelin is also degraded. Cuprizone-intoxicated mice show a controlled demyelination and remyelination in the CNS. The basic biochemical processes in this model have been investigated, and factors that may affect remyelination such as the presence of anti-MAG antibodies will now be studied. In most hypomyelinating mutant animals, proteins of compact myelin (MBP and PLP) are decreased more than proteins in associated membranes (MAG and CNP), regardless of the primary cause of the hypomyelination. This is true in most demyelinating mutants, including a PLP gene defect (shaking pup), a cholesterol storage disorder (CSD mice), and a congenital virus infection (Border disease in sheep). This pattern of change in myelin proteins was also found in two human patients with Niemann-Pick C disease, and is probably due to a greater deficiency of compact myelin than of associated oligodendroglial membranes. At the moment, we are studying a new neurological rat mutant, the TAIEP rat, which is different in this respect. It expresses very low amounts of MAG in comparison to other myelin proteins, and the MAG is only detectable as the immature large isoform. We are also currently studying brain biopsies from two young girls with severe hypomyelination due to unknown causes.
