Myelin surrounds many of the axons in the central and peripheral nervous systems where it facilitates the rapid conduction of nerve impulses and provides an extrinsic trophic effect that promotes axonal maturation and survival. Dysmyelination and demyelination are major causes of neurological disability in humans and can be fatal. Historically, neurological deficits in these primary myelin diseases were thought to result from myelin pathology. However, recent studies have identified axonal degeneration in a number of primary myelin diseases. 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 overexpressed. We have developed transgenic mouse models of PNS and CNS dysmyelination by overexpressing P0 protein, the major structural protein of PNS myelin in Schwann cells, and by expressing high levels of P0 protein in myelinating oligodendrocytes. The overall goal of this application is to understand how P0 overexpression causes myelin and axonal pathology. Schwann cells that overexpress P0 protein ensheath but fail to myelinate axons because they mistarget P0 to non-myelin surface membranes. Studies in Specific Aim 1 will investigate mechanisms responsible for P0 and MAG targeting in MDCK cells in vitro.
Specific Aim 2 will investigate how dysmyelination in P0 overexpressing mice causes alteration in ion channel distribution in PNS axons and a distal axonopathy that consists of axonal withdrawal from the neuromuscular junction and subsequent axonal sprouting and neuromuscular junction reinnervation. We have also established that P0 expression by oligodendrocytes results in CNS dysmyelination and axonal degeneration.
Specific Aim 3 will investigate molecular mechanisms responsible for these pathologies and determine if the phenotype is rescued by their breeding to PLP null mice. Collectively, these studies should provide novel information about the pathogenesis of dysmyelination, molecular mechanisms of normal myelination, and the mechanisms by which myelin-forming cells modulate the development and survival of axons.
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