In many genetic disorders of myelin, neuropathological abnormalities are well documented, particularly for the terminal stage. In some, such as metachromatic leukodystrophy or globoid cell leukodystrophy, the underlying enzymatic defects have been identified. Nevertheless, there is a large gap in our understanding of the pathogenetic mechanisms of these disorders that lead from the fundamental genetic defects to the eventual clinical, pathological and biochemical manifestations. This application proposes to investigate such pathogenetic mechanisms primarily with morphological approaches including the transmission electron microscopy, the freeze-fracture technique, immunocytochemistry, and the tissue culture. One important general approach is the detailed morphological studies in the early stages of the disease. Two murine models of genetic myelin disorders will be utilized. The twitcher mutant is an enzymatically authentic model of human globoid cell leukodystrophy. Careful examination of the earliest stages of the disease will be carried out in order to understand the chronological sequence of pathological changes. Such studies are not possible with human patients. Effects of suppression of the globoid cell reaction by means of cycloheximide and silica dust and also the effects of supplementation of the missing enzyme, galactosylceramidase, will be examined. Immunocytochemistry for known surface antigens of different cell types will be used to identify the nature of the globoid cells. The second murine model is the quaking mutant, which has no known human counterpart but is a unique genetic myelin disorder. We described abnormally large number of interlamellar tight junctions (the radial component) in the CNS myelin of affected animals. Similar tight junctions have been noted in various human myelin disorders, but their functional significance is not clear. Detailed developmental studies of the radial component and its modifications under experimental conditions will be investigated in the affected as well as normal mice. The experimental manipulations will include chemical and mechanical (Wallerian) demyelination. The results of these projects should provide us with not only the understanding of the sequence of pathological events in these particular disorders but also with broader understanding of formation and maintenance of myelin in general.
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