Generalized CNS Disease and Massive GM1-Ganglioside Accumulation in Mice Defective in Lysosomal Acid -galactosidase

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Abstract
Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid β-galactosidase (β-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional β-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of β-gal mRNA and totally deficient in GM1-ganglioside-hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff-positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulation of GM1-ganglioside in the brain progressed from twice to almost five times the normal amount during the period from 3 weeks to 3.5 months. Despite the accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice show no overt clinical phenotype up to 4–5 months. However, tremor, ataxia and abnormal gait become apparent in older mice. Thus, the β-gal-deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.