Proteins And Proteolytic Enzymes Of Myelin

Since this chapter deals essentially with the role of proteolytic enzymes in myelin breakdown, it is important to briefly review the structural proteins of CNS and PNS myelin which together with lipids maintain the integrity of the myelin sheath. Several important CNS proteinases partially responsible for destabilizing the myelin sheath in diseases will also be reviewed.

Myelin is largely composed of lipids (70%) and proteins (30%). The two major proteins of myelin are myelin basic protein (MBP) and proteolipid protein (PLP) which constitute 30% and 50% of all myelin proteins, respectively. PLP (24kD molecular weight) is tightly bound to lipids while MBP (18kD molecular weight) is also complexed with lipids, but with less affinity than PLP16. Minor myelin proteins with important roles include MAG (myelin-associated glycoprotein) MOG (myelin oligodendrocyte-specific glycoprotein), MOBP (myelin oligodendrocyte-specific basic protein), and DM-20 of the PLP family of proteins. Proteinases, lipases, kinases, and peptidases are also present 13>17-22. MBP is highly susceptible to proteolysis and is digested by cathepsin B and D, calpain, metalloproteinase, trypsin, and pepsin while PLP is resistant to trypsin. The latter however, is partially digested by elastase23, trypsin and calpain, if detergent is present23-26 . The intact MBP, PLP, and MOG proteins or their proteolyzed fragments when injected into susceptible animals result in an autoimmune demyelinating disease, experimental allergic encephalomyelitis (EAE) a model for human multiple sclerosis (MS).

PNS myelin also contains MBP along with P0 protein, which is similar to CNS PLP. MAG and other minor enzyme proteins, proteinases, and lipases are present as well. One of the myelin basic proteins, P2 protein, is resistant to endogenous CNS and PNS proteinases. However, P2 can be degraded by cathepsin D and MPC, in the presence of a detergent. The P2 protein, intact or fragmented, has been found to cause an autoimmune demyelinating disease of PNS, experimental allergic neuritis (EAN), which has been used as a model for Guillain Barre Syndrome, the PNS demyelinating disease of humans.

Proteinase Hypothesis

Acid proteinase activity was demonstrated in CNS samples in the early 1930s and 1940s2728. Subsequently lysosomal proteinases cathepsins A, B, and D were purified from brain samples with increased activities of these proteases observed in diseases29-32. Cathepsin D was found to degrade phenylalanine-phenylalanine linkages in MBP molecules. Acid proteinase activity was also found to be localized in neurons. In contrast to acid proteinases, the demonstration of non-lysosomal neutral proteinase activity in brain was difficult since they are more unstable than lysosomal proteinases. Nonetheless, in the 1950s and 1960s Ansell and Richter33 and Marks and Lajtha34 were able to determine neutral proteinase activity in brain samples35. Since then several neutral proteinases including MPC, calpain, and metalloproteinase activity were found in the brain and later purified 14,20-22,36-43 Aminopeptidases and arylamidases are also found in myelin29,44-47 . In contrast to CNS, the characterization ofproteinases in PNS is less extensive. The histochemical demonstration of proteinases in PNS was shown in the early 1960s24 followed by findings of calpain activity in sciatic nerve and Schwann cells4849. Later, an unidentified neutral proteinase capable of degrading the Po protein of PNS was also demonstrated50. The characterization of these various proteinases suggested myelin may be metabolically active and even autodigestive in demyelinating diseases.

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