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.lysosomal storage disorder ͉ glucocerebrosidase deficiency ͉ neurodegeneration ͉ knockout mice ͉ gene therapy

Neonatal Bone Marrow Transplantation in MPS IIIA Mice

“…This concept is supported by data generated in mouse models of Gaucher disease that either expressed glucosylceramidase activity in the microglia (and skin) or in skin fibroblasts only (Enquist et al 2007). Both models showed neurological abnormalities, with only marginal delays in the onset of symptoms and minimal impact on life span.…”

CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy

“…This difference suggests that an alternative or more complex pathogenic mechanism underlies the neuroinflammatory process in synucleinopathies and neuropathic Gaucher disease. Another explanation might be that the pathological insult in Gba1 D409V/D409V mice is relatively mild, as more severely affected Gaucher mice and transgenic mice overexpressing α-syn do display glial activation, particularly at late stages of disease after neuronal death has occurred (20,26,31,32).…”

“…mice contained less than 10% residual glucocerebrosidase activity and accumulate both GlcCer and GlcSph. Concomitant with these changes was the development of neurodegenerative disease leading to death by postnatal day 14 (31,32). Consequently, further studies were restricted to heterozygous Gba1 +/− mice that retain ∼54% of wild-type GBA1 activity (Table 1).…”

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

“…In fact, a homozygous mutation in human β-glucocerebrosidase (GBA1), a crucial enzyme degrading β-GlcCer, leads to Gaucher disease because of a reduction in enzyme activity that causes accumulation of β-GlcCer (19). Gaucher disease is characterized by systemic inflammation, which presents hepatosplenomegaly or neurodegeneration (20)(21)(22)(23)(24). However, the molecular mechanisms that link excessive β-GlcCer to inflammatory responses are not yet understood.…”