Murine models of acute neuronopathic Gaucher disease

作者：Enquist Ida Berglin; Lo Bianco Christophe; Ooka Andreas; Nilsson Eva; Mansson Jan Eric; Ehinger Mats; Richter Johan; Brady Roscoe O; Kirik Deniz; Karlsson Stefan^*

来源：Proceedings of the National Academy of Sciences, 2007, 104(44): 17483-17488.

DOI：10.1073/pnas.0708086104

• lysosomal storage disorder
• glucocerebrosidase deficiency
• neurodegeneration
• knockout mice
• gene therapy

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.

• 出版日期2007-10-30