Myelin surrounds many of the axons in the central and peripheral neurons systems where it facilitates the rapid conduction of nerve impulses and provides an extrinsic trophic effect that promotes axonal maturation and survival. Failure to form myelin and destruction of mature myelin are major causes of neurological disability in humans and can be fatal. Historically, neurological deficits in these primary myelin disease were thought to result from myelin pathology. However, recent studies have identified axonal degeneration in large number of primary myelin diseases. Mutations in myelin protein genes are responsible for many myelin diseases. These include point mutations, stop codons, duplications and deletions. The most common causes of genetic myelin disease in humans are gene duplications that alter the dosage of myelin proteins. Much of what is known about the cellular and molecular aspects of normal myelination and the pathogenesis of inherited myelin diseases has been obtained from studies of rodents in which myelin protein genes are mutated, deleted or over expressed. We have developed transgenic mouse models of PNS and CNS dysmyelination by 1) over expressing P0 protein, the major structural protein of PNS myelin in Schwann cells, and 2) expressing high levels of P0 protein in myelinating oligodendrocytes. Schwann cells in P0 over expressing mice fail to myelinate and, as a consequence, motor axons degenerate. Preliminary studies suggest that dysmyelination results from mistargeting of P0 protein to non-myelin surface membranes. Studies in Specific Aim 1 will rigorously test this hypothesis and investigate the mechanism by which axons degenerate. Expression of P0 in oligodendrocytes results in a dysmyelination that includes redundant myelin membranes and possible axonal degeneration. Studies in Specific aim 2 of this proposal will investigate the molecular mechanisms responsible for this dysmyelination and compare and contrast the effects of P0 expression in oligodendrocytes with PLP over expression in oligodendrocytes and P0 over expression in Schwann cells. Collectively, these studies should provide novel information about the pathogenesis of dysmyelination, molecular mechanism of normal myelination, and he mechanisms by which myelin-forming cells modulate the development and survival of axons.
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