Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos
Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease) indica...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
December 2024
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| In: |
Computational and structural biotechnology journal
Year: 2024, Volume: 23, Pages: 1397-1407 |
| ISSN: | 2001-0370 |
| DOI: | 10.1016/j.csbj.2024.03.023 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.csbj.2024.03.023 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S200103702400076X 
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| Author Notes: | Jessica Guerra, Mirella Belleri, Giulia Paiardi, Chiara Tobia, Davide Capoferri, Marzia Corli, Elisa Scalvini, Marco Ghirimoldi, Marcello Manfredi, Rebecca C. Wade, Marco Presta, Luca Mignani |
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| 245 | 1 | 0 | |a Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |c Jessica Guerra, Mirella Belleri, Giulia Paiardi, Chiara Tobia, Davide Capoferri, Marzia Corli, Elisa Scalvini, Marco Ghirimoldi, Marcello Manfredi, Rebecca C. Wade, Marco Presta, Luca Mignani |
| 246 | 3 | 3 | |a Impact of an irreversible beta-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| 264 | 1 | |c December 2024 | |
| 300 | |b Illustrationen, Diagramme | ||
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| 520 | |a Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease) indicate that the pathogenesis of this disorder is the consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine), ignoring the possibility that this enzyme may exert a wider biological impact. Indeed, limited information is available about the effect of GALC downregulation on the cell lipidome in adult and developing organisms. The teleost zebrafish (Danio rerio) has emerged as a useful platform to model human genetic diseases, including sphingolipidoses, and two GALC co-orthologs have been identified in zebrafish (galca and galcb). Here, we investigated the effect of the competitive and irreversible GALC inhibitor β-galactose-cyclophellitol (GCP) on the lipid profile of zebrafish embryos. Molecular modelling indicates that GCP can be sequestered in the catalytic site of the enzyme and covalently binds human GALC, and the zebrafish Galca and Galcb proteins in a similar manner. Accordingly, GCP inhibits the β-galactosylceramide hydrolase activity of zebrafish in vitro and in vivo, leading to significant alterations of the lipidome of zebrafish embryos. These results indicate that the lack of GALC activity deeply affects the lipidome during the early stages of embryonic development, and thereby provide insights into the pathogenesis of Krabbe disease. | ||
| 650 | 4 | |a Galactosylceramidase | |
| 650 | 4 | |a Krabbe disease | |
| 650 | 4 | |a Lipidomics | |
| 650 | 4 | |a Molecular modeling | |
| 650 | 4 | |a Zebrafish | |
| 700 | 1 | |a Belleri, Mirella |e VerfasserIn |4 aut | |
| 700 | 1 | |a Paiardi, Giulia |e VerfasserIn |0 (DE-588)1236143736 |0 (DE-627)1761324675 |4 aut | |
| 700 | 1 | |a Tobia, Chiara |e VerfasserIn |4 aut | |
| 700 | 1 | |a Capoferri, Davide |e VerfasserIn |4 aut | |
| 700 | 1 | |a Corli, Marzia |e VerfasserIn |4 aut | |
| 700 | 1 | |a Scalvini, Elisa |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ghirimoldi, Marco |e VerfasserIn |4 aut | |
| 700 | 1 | |a Manfredi, Marcello |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Presta, Marco |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mignani, Luca |e VerfasserIn |4 aut | |
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