GENERALIZED CNS DISEASE AND MASSIVE G(M1)-GANGLIOSIDE ACCUMULATION INMICE DEFECTIVE IN LYSOSOMAL ACID BETA-GALACTOSIDASE

Human G(M1)-gangliosidosis is caused by a genetic deficiency of lysoso mal acid beta-galactosidase (beta-gal), The disease manifests itself e ither as an infantile, juvenile or adult form and is primarily a neuro logical disorder with progressive brain dysfunction. A mouse model lac king a functional beta-gal gene has been generated by homologous recom bination and embryonic stem cell technology, Tissues from affected mic e are devoid of beta-gal mRNA and totally deficient in G(M1)-gangliosi de-hydrolyzing capacity. Storage material was already conspicuous in t he brain at 3 weeks, By 5 weeks, extensive storage of periodic acid Sc hiff-positive material was observed in neurons throughout the brain an d spinal cord, Consistent with the neuropathology, abnormal accumulati on of G(M1)-ganglioside in the brain progressed from twice to almost f ive times the normal amount during the period from 3 weeks to 3.5 mont hs, Despite the accumulation of brain G(M1)-ganglioside at the level e qual to or exceeding that seen in gravely ill human patients, these mi ce show no overt clinical phenotype up to 4-5 months. However, tremor, ataxia and abnormal gait become apparent in older mice, Thus, the bet a-gal-deficient mice appear to mimic closely the pathological, biochem ical and clinical abnormalities of the human disease.