Studies on the β-galactosidosis using transgenic mice expressing ganglioside-related glycogenes

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β-Galactosidosis comprises clinically different diseases, GM1-gangliosidosis and Morquio B disease, both of which are caused by deficiency of lysosomal acid β-galactosidase (β-Gal). We focused on GM1-gangliosidosis, a neurogenetic disease occurring mainly in early infancy, and rarely in childhood or young adults. In this study, we generated the model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C on the β-Gal KO background. The model mice exhibited slowly progressive neurological deterioration, such as tremor and gait disturbance from 9 months of age and died around 15 months. Storage of ganglioside GM1 in their brains was less abundant than in the β-Gal KO mouse brain. Using this mouse, we examined the possibility of chemical chaperone therapy. Oral administration of newly synthesized β-Gal inhibitor to the juvenile GM1-gangliosidosis model mice resulted in significant enhancement of the enzyme activity in the brain and other tissues. Although mass biochemical analysis did not show the reduction of GM1 in the brain in this short term trial (1 week), chemical chaperone therapy may be useful for certain patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement. We also generated the transgenic mice expressing GM1/GA1 synthase gene and tried to introduce the transgene into β-Gal KO mice in order to accelerate their disease onset. We injected the transgene fragments (3.5 kb) containing CAG promoter and mouse GM1/GA1 synthase cDNA (1.2 kb) into fertilized oocytes of C57BL/6J mice. We produced 4 lines of transgenic mice expressing the transgene at least in the liver and the brain. GM1 was detected in the liver of 3 transgenic mouse lines, although no GM1 was detectable in non-transgenic C57BL/6 mice. We are currently evaluating the effect of the over expression of GM1/GA1 synthase on the disease onset by introducing the transgene into β-Gal KO mice.