Long-term objectives of the studies proposed in this application are to investigate pathogenesis and cellular mechanisms of the disease processes in metabolic neurodegenerative disorders and to explore the possibilities of therapeutic manipulation of the disease processes. The animal model used for the studies in the current proposal is a twitcher mouse, an enzymatically and pathologically authentic murine model of globoid cell leukodystrophy (GLD) in humans.
Specific aims to be investigated are as follows: 1) Investigation on the therapeutic effects of enzyme supplementation on the central and peripheral nervous tissues (PNS and CNS). The following experiments will be conducted: a) Transplantation of twitcher nervous tissue into normal mouse brain to evaluate the survival and improvement of metabolically abnormal tissue within the normal environment, b) Implantation of twitcher Schwann cells to enzymatically normal mouse brain or spinal cord to evaluate the behavior of metabolically abnormal myelin forming cells within the enzymatically normal environment, c) Implantation of normal embryonic nervous tissue into the brain and spinal cord of twitcher mouse to evaluate the effect of enzyme supplementation on abnormal nervous tissue and d) Infusion of macrophages from normal mice into the subarachnoid space of twitcher to evaluate these macrophages as a possible carrier for the enzyme transport into the pathological nervous tissue. 2) Investigation on the mechanism of unique cellular response of twitcher nervous system to demyelination and/or Wallerian degeneration. In demyelinating twitcher PNS, Schwann cells of unmyelinated fibers showed remarkable morphological alterations by extending and branching their processes. Also in Wallerian degeneration of twitcher PNS, myelin debris disappeared very rapidly compared with controls. Mechanisms of these two phenomena will be further investigated with immunocytochemistry and electron microscopy, using in vivo and in vitro systems.
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