title: Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase.
abstract: Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-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 beta-gal gene has been generated by homologous recombination and embryonic stem cell technology. Tissues from affected mice are devoid of beta-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 beta-gal-deficient mice appear to mimic closely the pathological, biochemical and clinical abnormalities of the human disease.
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Hahn
authors.forename: M
authors.initials: M
authors.lastname: del Pilar Martin
authors.forename: M
authors.initials: M
authors.lastname: Schröder
authors.forename: M T
authors.initials: MT
authors.lastname: Vanier
authors.forename: Y
authors.initials: Y
authors.lastname: Hara
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D005677:G(M1) Ganglioside / Q000378:metabolism*; D005732:Gangliosides; D016537:Gangliosidosis, GM1 / Q000378:metabolism*; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D001616:beta-Galactosidase / Q000172:deficiency* / Q000235:genetics
chemical_list: C011258:G(A1) ganglioside; D005732:Gangliosides; D006028:Glycosphingolipids; D005677:G(M1) Ganglioside; D001616:beta-Galactosidase