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Animal Models for the Study of Gaucher Disease

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 accumul...

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Autores principales: Cabasso, Or, Kuppuramalingam, Aparna, Lelieveld, Lindsey, Van der Lienden, Martijn, Boot, Rolf, Aerts, Johannes M., Horowitz, Mia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671165/
https://www.ncbi.nlm.nih.gov/pubmed/38003227
http://dx.doi.org/10.3390/ijms242216035
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author Cabasso, Or
Kuppuramalingam, Aparna
Lelieveld, Lindsey
Van der Lienden, Martijn
Boot, Rolf
Aerts, Johannes M.
Horowitz, Mia
author_facet Cabasso, Or
Kuppuramalingam, Aparna
Lelieveld, Lindsey
Van der Lienden, Martijn
Boot, Rolf
Aerts, Johannes M.
Horowitz, Mia
author_sort Cabasso, Or
collection PubMed
description 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.
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spelling pubmed-106711652023-11-07 Animal Models for the Study of Gaucher Disease Cabasso, Or Kuppuramalingam, Aparna Lelieveld, Lindsey Van der Lienden, Martijn Boot, Rolf Aerts, Johannes M. Horowitz, Mia Int J Mol Sci Review 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. MDPI 2023-11-07 /pmc/articles/PMC10671165/ /pubmed/38003227 http://dx.doi.org/10.3390/ijms242216035 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Cabasso, Or
Kuppuramalingam, Aparna
Lelieveld, Lindsey
Van der Lienden, Martijn
Boot, Rolf
Aerts, Johannes M.
Horowitz, Mia
Animal Models for the Study of Gaucher Disease
title Animal Models for the Study of Gaucher Disease
title_full Animal Models for the Study of Gaucher Disease
title_fullStr Animal Models for the Study of Gaucher Disease
title_full_unstemmed Animal Models for the Study of Gaucher Disease
title_short Animal Models for the Study of Gaucher Disease
title_sort animal models for the study of gaucher disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671165/
https://www.ncbi.nlm.nih.gov/pubmed/38003227
http://dx.doi.org/10.3390/ijms242216035
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