This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. IIn 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 lifespans and no axonal degeneration. The purpose of the proposed investigation is 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 can be tested with the high voltage microscope and thick sections routinely used at the NCMIR. A second project involves looking at the spinal cord from multiple sclerosis (MS) patients Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in MS patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. Dr. Perkins will help us to characterize the structural abnormalities of mitochondria present in MS spinal cord using electron tomography.
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