title: Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid beta-glucosidase residual activity levels.
abstract: Genetic and chemically induced neuronopathic mouse models of Gaucher disease were developed to facilitate understanding of the reversibility and/or progression of CNS involvement. The lethality of the skin permeability barrier defect of the complete gene knock out [gba, (glucocerebrosidase) GCase] was avoided by conditional reactivation of a low activity allele (D409H) in keratinocytes (kn-9H). In kn-9H mice, progressive CNS disease and massive glucosylceramide storage in tissues led to death from CNS involvement by the age of 14 days. Conduritol B epoxide (CBE, a covalent inhibitor of GCase) treatment (for 8-12 days) of wild type, D409H, D409V or V394L homozygotes recapitulated the CNS phenotype of the kn-9H mice with seizures, tail arching, shaking, tremor, quadriparesis, extensive neuronal degeneration loss and apoptosis, and death by the age of 14 days. Minor CNS abnormalities occurred after daily CBE injections of 100 mg/kg/day for 6 doses, but neuronal degeneration was progressive and glucosylceramide storage persisted in D409V homozygotes in the 2 to 5 months after CBE cessation; wild type and D409H mice had persistent neurological damage without progression. The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement.
authors.affiliation: The Divisions of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH 45229-3039, USA.
authors.forename: You-Hai
authors.initials: YH
authors.lastname: Xu
authors.forename: Rachel
authors.initials: R
authors.lastname: Reboulet
authors.forename: Brian
authors.initials: B
authors.lastname: Quinn
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005962:Glucosylceramidase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D007294:Inositol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: D016207:Cytokines; D005963:Glucosylceramides; D006028:Glycosphingolipids; D007294:Inositol; D005962:Glucosylceramidase; C011423:conduritol epoxide