Development of lysosomal storage in mice with targeted disruption of the β-galactosidase gene: a model of human GM1-gangliosidosis

A deficiency of lysosomal acid β-galactosidase leads to GM1-gangliosidosis in humans, which progressively and profoundly affects the brain and other organs mainly in the early infantile period. We report the pathology of mice with targeted disruption of the β-galactosidase gene. In the central nervous system, vacuolated neurons appeared in the spinal cord 3 days after birth. The vacuolation extended to neurons in the brainstem, cerebral cortex, hippocampus and thalamus and ballooning neurons became prominent with age. The vacuolation also appeared in Purkinje cells without a marked ballooning change. Reactive astrogliosis in the entire brain was marked at the terminal stage of the disease. Immunohistochemical study using anti-ganglioside GM1 and GA1 antibodies revealed extensive accumulation of GM1 and GA1 in the cerebral neurons. In the liver, however, accumulation of GM1 was localized in the cytoplasm of hepatocytes, whereas that of GA1 was localized in foamy macrophages and Kupffer cells. There were no significant abnormalities in the bone, bone marrow, or cornea at any stage. Although there are some phenotypic and biochemical differences between this knockout mouse and human GM1 gangliosidosis, the mouse will be a useful model for therapeutic trials for the human disease.