MOLECULAR MECHANISMS OF SCHWANN CELL MYELINATION
Principal Investigator: Bruce Trapp
Affiliation: Cleveland Clinic Foundation
Abstract: 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.
Funding Period: 1999-03-01 - 2002-03-31
more information: NIH RePORT
- Structure and stability of internodal myelin in mouse models of hereditary neuropathyRobin L Avila
Biology Department, Boston College, Chestnut Hill, MA 02467, USA
J Neuropathol Exp Neurol 64:976-90. 2005..Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies...
- Evolution of a neuroprotective function of central nervous system myelinXinghua Yin
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
J Cell Biol 172:469-78. 2006..These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia...
- A dual tyrosine-leucine motif mediates myelin protein P0 targeting in MDCK cellsGrahame J Kidd
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
Glia 54:135-45. 2006..The results indicate that P0 contains a hierarchy of targeting signals, which may contribute to P0 localization in myelinating Schwann cells and the pathogenesis in human disease...
- Axon-glial signaling and the glial support of axon functionKlaus Armin Nave
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D 37075 Gottingen, Germany
Annu Rev Neurosci 31:535-61. 2008..Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems...