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.
|Hiremath, Meenaxi M; Chen, Vivian S; Suzuki, Kinuko et al. (2008) MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 203:23-32|
|Kagitani-Shimono, Kuriko; Mohri, Ikuko; Yagi, Takashi et al. (2008) Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels. Acta Neuropathol 115:577-87|
|Mohri, Ikuko; Taniike, Masako; Taniguchi, Hidetoshi et al. (2006) Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. J Neurosci 26:4383-93|
|Mohri, Ikuko; Taniike, Masako; Okazaki, Issei et al. (2006) Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides. J Neurochem 97:641-51|
|Kagitani-Shimono, K; Mohri, I; Oda, H et al. (2006) Lipocalin-type prostaglandin D synthase (beta-trace) is upregulated in the alphaB-crystallin-positive oligodendrocytes and astrocytes in the chronic multiple sclerosis. Neuropathol Appl Neurobiol 32:64-73|
|Langmade, S Joshua; Gale, Sarah E; Frolov, Andrey et al. (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci U S A 103:13807-12|
|Yagi, Takashi; Matsuda, Junko; Tominaga, Kumiko et al. (2005) Hematopoietic cell transplantation ameliorates clinical phenotype and progression of the CNS pathology in the mouse model of late onset Krabbe disease. J Neuropathol Exp Neurol 64:565-75|
|Wu, Yun-Ping; Mizukami, Hiroki; Matsuda, Junko et al. (2005) Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. Mol Genet Metab 84:9-17|
|Takikita, Shoichi; Fukuda, Takahiro; Mohri, Ikuko et al. (2004) Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J Neuropathol Exp Neurol 63:660-73|
|Saito, Yuko; Suzuki, Kinuko; Hulette, Christine M et al. (2004) Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J Neuropathol Exp Neurol 63:323-8|
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