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Murine models of acute neuronopathic Gaucher disease

Berglin-Enquist, Ida LU ; Lobianco, Christophe LU ; Ooka, Andreas LU ; Nilsson, Eva C LU ; Mansson, Jan-Eric ; Ehinger, Mats LU ; Richter, Johan LU ; Brady, Roscoe O. ; Kirik, Deniz LU orcid and Karlsson, Stefan LU orcid (2007) In Proceedings of the National Academy of Sciences 104(44). p.17483-17488
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,... (More)
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. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
neurodegeneration, lysosomal storage disorder, glucocerebrosidase deficiency, gene therapy, knockout mice
in
Proceedings of the National Academy of Sciences
volume
104
issue
44
pages
17483 - 17488
publisher
National Academy of Sciences
external identifiers
  • wos:000250638400046
  • scopus:36849057499
ISSN
1091-6490
DOI
10.1073/pnas.0708086104
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Molecular Medicine and Gene Therapy (013022010), Faculty of Medicine (000022000), Brain Repair and Imaging in Neural Systems (BRAINS) (013212027), Pathology, (Lund) (013030000)
id
1c3e14d9-922b-4ab6-a681-95e5320d10b2 (old id 651807)
date added to LUP
2016-04-01 11:58:28
date last changed
2025-01-16 02:10:53
@article{1c3e14d9-922b-4ab6-a681-95e5320d10b2,
  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.}},
  author       = {{Berglin-Enquist, Ida and Lobianco, Christophe and Ooka, Andreas and Nilsson, Eva C and Mansson, Jan-Eric and Ehinger, Mats and Richter, Johan and Brady, Roscoe O. and Kirik, Deniz and Karlsson, Stefan}},
  issn         = {{1091-6490}},
  keywords     = {{neurodegeneration; lysosomal storage disorder; glucocerebrosidase deficiency; gene therapy; knockout mice}},
  language     = {{eng}},
  number       = {{44}},
  pages        = {{17483--17488}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences}},
  title        = {{Murine models of acute neuronopathic Gaucher disease}},
  url          = {{http://dx.doi.org/10.1073/pnas.0708086104}},
  doi          = {{10.1073/pnas.0708086104}},
  volume       = {{104}},
  year         = {{2007}},
}