This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The resources at the NCMIR are invaluable for examining the three-dimensional transport along myelinated axons. In the vertebrate nervous system, myelin is a multilayer membrane insulation that surrounds axons and promotes rapid nerve communication. We are investigating genetically engineered mice that express P0 instead of PLP in CNS glia. Surprisingly, in the absence of PLP, P0 provided a well ordered structure to mouse CNS myelin, but the ordered structure resembled that found in mammalian peripheral nervous system (PNS) myelin where P0 is the major structural protein. Thus, the presence or absence of PLP and P0 appears to define the ordered structure of myelin. However, the lifespan of these mice was reduced by 50%, presumably because of the axonal degeneration. Mice with equal amounts of P0 and PLP in CNS myelin had normal life spans and no axonal degeneration. We are using electron microscopy to elucidate changes in the myelinated axon that precede axonal degeneration. Preliminary studies indicate alterations in the axonal transport at or near nodes of Ranvier. We suspect that the 3-dimentional organization of axonal cytoskeleton is altered in nodal regions. This hypothesis is being tested with the high voltage microscope and thick sections routinely used at the NCMIR. Three-dimensional reconstructions are being generated from tilt series.
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