Murine models of acute neuronopathic Gaucher disease

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Murine models of acute neuronopathic Gaucher disease. / Berglin-Enquist, Ida; Lobianco, Christophe; Ooka, Andreas; Nilsson, Eva C; Mansson, Jan-Eric; Ehinger, Mats; Richter, Johan; Brady, Roscoe O.; Kirik, Deniz; Karlsson, Stefan.

In: Proceedings of the National Academy of Sciences, Vol. 104, No. 44, 2007, p. 17483-17488.

Research output: Contribution to journalArticle

Harvard

Berglin-Enquist, I, Lobianco, C, Ooka, A, Nilsson, EC, Mansson, J-E, Ehinger, M, Richter, J, Brady, RO, Kirik, D & Karlsson, S 2007, 'Murine models of acute neuronopathic Gaucher disease', Proceedings of the National Academy of Sciences, vol. 104, no. 44, pp. 17483-17488. https://doi.org/10.1073/pnas.0708086104

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Berglin-Enquist I, Lobianco C, Ooka A, Nilsson EC, Mansson J-E, Ehinger M et al. Murine models of acute neuronopathic Gaucher disease. Proceedings of the National Academy of Sciences. 2007;104(44):17483-17488. https://doi.org/10.1073/pnas.0708086104

Author

Berglin-Enquist, Ida ; Lobianco, Christophe ; Ooka, Andreas ; Nilsson, Eva C ; Mansson, Jan-Eric ; Ehinger, Mats ; Richter, Johan ; Brady, Roscoe O. ; Kirik, Deniz ; Karlsson, Stefan. / Murine models of acute neuronopathic Gaucher disease. In: Proceedings of the National Academy of Sciences. 2007 ; Vol. 104, No. 44. pp. 17483-17488.

RIS

TY - JOUR

T1 - Murine models of acute neuronopathic Gaucher disease

AU - Berglin-Enquist, Ida

AU - Lobianco, Christophe

AU - Ooka, Andreas

AU - Nilsson, Eva C

AU - Mansson, Jan-Eric

AU - Ehinger, Mats

AU - Richter, Johan

AU - Brady, Roscoe O.

AU - Kirik, Deniz

AU - Karlsson, Stefan

N1 - 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)

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - neurodegeneration

KW - lysosomal storage disorder

KW - glucocerebrosidase deficiency

KW - gene therapy

KW - knockout mice

U2 - 10.1073/pnas.0708086104

DO - 10.1073/pnas.0708086104

M3 - Article

VL - 104

SP - 17483

EP - 17488

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 44

ER -