title: Murine models of acute neuronopathic Gaucher disease.
abstract: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.
authors.affiliation: Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and the Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, BMC A12, 221 84 Lund, Sweden.
authors.forename: Ida Berglin
authors.initials: IB
authors.lastname: Enquist
authors.forename: Christophe
authors.initials: C
authors.lastname: Lo Bianco
authors.forename: Andreas
authors.initials: A
authors.lastname: Ooka
authors.forename: Eva
authors.initials: E
authors.lastname: Nilsson
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Månsson
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D015415:Biomarkers; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007438:Introns / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D012326:RNA Splicing / Q000235:genetics
chemical_list: D015415:Biomarkers; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D005962:Glucosylceramidase