Development of lysosomal storage in mice with targeted disruption of the beta-galactosidase gene: a model of human G(M1)-gangliosidosis

A deficiency of lysosomal acid beta -galactosidase leads to G(M1)-gangliosi dosis in humans, which progressively and profoundly affects the brain and o ther organs mainly in the early infantile period. We report the pathology o f mice with targeted disruption of the beta -galactosidase gene. In the cen tral 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 w ith age. The vacuolation also appeared in Purkinje cells without a marked b allooning change. Reactive astrogliosis in the entire brain was marked at t he terminal stage of the disease. Immunohistochemical study using anti-gang lioside G(M1) and G(A1) antibodies revealed extensive accumulation of G(M1) and G(A1) at in the cerebral neurons. In the liver, however, accumulation of G(MI) was localized in the cytoplasm of hepatocytes, whereas that of G(A 1) was localized in foamy macrophages and Kupffer cells. There were no sign ificant abnormalities in the bone, bone marrow, or cornea at any stage. Alt hough there are some phenotypic and biochemical differences between this kn ockout mouse and human GM1 gangliosidosis, the mouse will be a useful model for therapeutic trials for the human disease. 2001 Elsevier Science B.V. A ll rights reserved.