Molecular pathogenesis of congenital muscular dystrophies and development of new therapeutic measures

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Dystroglycan (DG) links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several congenital muscular dystrophies and aberrant glycosylation of α-DG has been implicated in their pathogeneses (α-dystroglycanopathy). In this study, we have obtained several novel findings concerning the molecular pathogenesis of a-dystroglycanopathy.(1) We found the protease activity that degrades the extracellular domain of β-DG specifically. This activity was suppressed by the inhibitor of MMP-2 and MMP-9. Cultured cells secreted MMP-2 and MMP-9 into the culture medium. Active MMP-2 and MMP-9 enzymes degraded the β-DG. MMP-2 and MMP-9 were activated in Duchenne muscular dystrophy and sarcoglycanopathyas well as in their model animals. These results indicate that inhibitors of MMP-2 and MMP-9 may be effective for these diseases.(2) Peripheral nerve myelination was defective in the fukutin-deficient chimeric mice, a mouse … More model of Fukuyama-type congenital muscular dystrophy. The density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non-myelinated axons were ensheathed by a single Schwann cell. The sugar chain moiety and laminin-binding activity of α-DG were severely reduced in the peripheral nerve of the chimeric mice. The clustering of acetylcholine receptor was defective and neuromuscular junctions are fragmented in appearance in these mice. These results demonstrate that dysmyelination of peripheral nerve should be carefully watched in congenital muscular dystrophies.(3) We found the cleavage and secretion of the N-terminal domain of α-DG (α-DG-N). Secreted α-DG-N was both N- and 0-glycosylated.α-DG-N was detectable in the human serum and cerebrospinal fluid. These observations indicate that the cleavage of α-DG-N is a widespread event and suggest that the secreted α-DG-N might be transported via systemic circulation and that the level of α-DG-N may be altered in α-dystroglycanopathies. Less