Animal Models for the Study of Gaucher Disease

Or Cabasso, Aparna Kuppuramalingam, Lindsey Lelieveld, Martijn Van der Lienden, Rolf Boot, Johannes M. Aerts*, Mia Horowitz*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations


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.

Original languageEnglish
Article number16035
JournalInternational Journal of Molecular Sciences
Issue number22
StatePublished - Nov 2023


FundersFunder number
Pfizer Pharmaceuticals
Fund for Innovation in Cancer Informatics00029


    • ER stress
    • GBA1
    • glucocerebrosidase (GCase)
    • glucosylceramide (GlcCer)
    • inflammation
    • knockin animals
    • knockout animals
    • misfolding
    • unfolded protein response (UPR)


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