Animal Models for the Study of Gaucher Disease

Int J Mol Sci. 2023 Nov 7;24(22):16035. doi: 10.3390/ijms242216035.


In Gaucher disease (GD), a relatively common sphingolipidosis, the mutant lysosomal enzyme acid β-glucocerebrosidase (GCase), encoded by the GBA1 gene, fails to properly hydrolyze the sphingolipid glucosylceramide (GlcCer) in lysosomes, particularly of tissue macrophages. As a result, GlcCer accumulates, which, to a certain extent, is converted to its deacylated form, glucosylsphingosine (GlcSph), by lysosomal acid ceramidase. The inability of mutant GCase to degrade GlcSph further promotes its accumulation. The amount of mutant GCase in lysosomes depends on the amount of mutant ER enzyme that shuttles to them. In the case of many mutant GCase forms, the enzyme is largely misfolded in the ER. Only a fraction correctly folds and is subsequently trafficked to the lysosomes, while the rest of the misfolded mutant GCase protein undergoes ER-associated degradation (ERAD). The retention of misfolded mutant GCase in the ER induces ER stress, which evokes a stress response known as the unfolded protein response (UPR). GD is remarkably heterogeneous in clinical manifestation, including the variant without CNS involvement (type 1), and acute and subacute neuronopathic variants (types 2 and 3). The present review discusses animal models developed to study the molecular and cellular mechanisms underlying GD.

Keywords: ER stress; GBA1; glucocerebrosidase (GCase); glucosylceramide (GlcCer); inflammation; knockin animals; knockout animals; misfolding; unfolded protein response (UPR).

Publication types

  • Review

MeSH terms

  • Animals
  • Gaucher Disease* / metabolism
  • Models, Animal
  • Mutation
  • Psychosine
  • Unfolded Protein Response


  • sphingosyl beta-glucoside
  • Psychosine