Analysis of the pathogenesis of neurodegenerative disorders using animal models with lysosomal lipid storage diseases.

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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.