2005 Fiscal Year Final Research Report Summary
Analysis of the pathogenesis of neurodegenerative disorders using animal models with lysosomal lipid storage diseases.
| Project/Area Number |
16300141
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | National Institute of Biomedical Innovation (2005)
National Institute of Infectious Diseases (2004) |
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Principal Investigator |
MATSUDA Junichiro National Institute of Biomedical Innovation, Department of Bioresources, Laboratory Head, 生物資源研究部, 研究リーダー (60181731)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Osamu National Institute of Biomedical Innovation, Department of Bioresources, Senior Researcher, 生物資源研究部, 主任研究員 (70235935)
TAKIMOTO Kazuhiro National Institute of Infectious Diseases, Division of Experimental Animals Research, Researcher, 動物管理室, 研究員 (70280766)
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| Project Period (FY) |
2004 – 2005
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| Keywords | glycolipid / gangliosidosis / β-galactosidase / lysosomal disease / disease model / transgenic mice / knockout mice / glycogene |
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| Research Abstract |
GM1-gangliosidosis is a progressive neurodegenerative disease caused by a deficiency of lysosomal beta-galactosidase (beta-Gal) resulting in progressive neural accumulation of GM1 ganglioside and its derivatives. Little is known about the mechanisms of neurodegeneration in this disease. In this study, we generated several transgenic(TG)/knockout (KO) mice including the GM1 synthase TG/beta-Gal KO mice and also we tried to analyze the pathogenesis of the disorder using these animal models. We established 4 lines of GM1 synthase TG mice and then successfully generated 3 lines of GM1 synthase TG/beta-Gal KO mice. Lipid analysis of one line of TG/KO mice revealed that the level of GM1 storage in their brains was almost same as the KO mice, although the ratio of GM1/asial GM1 storage was slightly increased in the TG/KO mice than that of the KO mice. The severity of the symptoms and the average life spans of these 3 lines of TG/KO mice were similar to those of the KO mice. For analysis of the pathogenesis, we used cerebellar granule cells from postnatal day 8 beta-Gal KO mice. These cells showed abnormal distribution of GM1 ganglioside in plasma membrane, which was accompanied by lysosomal GM1 accumulation. Since GM1 locates in lipid rafts and it is known to regulate Trk neurotrophin receptor-mediated signal transduction, we investigated its behavior in the brain of beta-Gal KO mice. By immunoprecipitation assay, the association of GM1 with Trk was proved to be defective and the phosphorylation of Trk A protein was significantly decreased in the cerebral cortex, midbrain and cerebellum of KO mice compared to wild type littermates. Consistent with this, downstream signaling from Trk A, namely Ca++ signaling via PLCgamma was also impaired. The impairment of Trk-related signaling may contribute to the loss of neuronal function and following neurodegeneration in GM1-gangliosidosis mouse brain.
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Research Products
(6 results)
