Abstract
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.
Keywords
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References
- β-Galactosidase deficiency (β-galactosidosis): GM1-Gangliosidosis and Morquio B disease.in: Scriver C.R Beaudet A.L Sly W.S Valle D Childs B Vogelstein B The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill, New York2001: 3775-3809
- GM1-gangliosidosis: chromosome 3 assignment of the beta-galactosidase-A gene (beta GALA).Somatic Cell Genet. 1979; 5: 147-158
- Lyosomal and peroxisomal disorders.in: Graham D.I Lantos P.L The Greenfields Neuropathology. 6th ed. Arnold, London1997: 657-753
- β-Galactosidase-deficient mouse as an animal model for GM1-gangliosidosis.Glycoconjugate J. 1997; 14: 729-736
- Neurological manifestations of knockout mice with β-galactosidase deficiency.Brain Dev. 1997; 19: 19-20
- Developmental changes of ganglioside expressions in postnatal rat cerebellar cortex.Brain Res. 1995; 700: 40-58
- Mouse models of Tay–Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism.Nat Genet. 1995; 11: 170-176
- Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay–Sachs disease.Acta Neuropathol. 1995; 89: 296-304
- Mouse models of human lysosomal diseases.Brain Pathology. 1998; 8: 195-215
- Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid β-galactosidase.Hum Mol Genet. 1997; 6: 205-211
- The degradative pathway of gangliosides GM1 and GA1 in Neuro2a cells by sialidase.J Neurochem. 1995; 64: 451-454
- Pathologic findings in fetal GM1 gangliosidosis.Arch Neurol. 1986; 43: 736-738
- Fetal GM1-gangliosidosis: morphological and biochemical studies.Brain Dev. 1989; 11: 394-398
- Prenatal diagnosis of lysosomal storage diseases.Brain Pathol. 1998; 8: 133-149
Article info
Publication history
Accepted:
June 18,
2001
Received in revised form:
June 18,
2001
Received:
August 11,
2000
Identification
Copyright
© 2001 Elsevier Science B.V. Published by Elsevier Inc. All rights reserved.
