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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S200103702400076X |
| _version_ | 1827291916998279168 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jessica Guerra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T12:47:13Z |
| format | Article |
| id | doaj.art-c98712cfb14b4da3a4a44f64229c80dd |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-24T12:47:13Z |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-c98712cfb14b4da3a4a44f64229c80dd2024-04-07T04:35:26ZengElsevierComputational and Structural Biotechnology Journal2001-03702024-12-012313971407Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryosJessica Guerra0Mirella Belleri1Giulia Paiardi2Chiara Tobia3Davide Capoferri4Marzia Corli5Elisa Scalvini6Marco Ghirimoldi7Marcello Manfredi8Rebecca C. Wade9Marco Presta10Luca Mignani11Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Germany; Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, GermanyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Center for Allergic and Autoimmune Diseases, University of Piemonte Orientale, Novara, ItalyDepartment of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Center for Allergic and Autoimmune Diseases, University of Piemonte Orientale, Novara, ItalyMolecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Germany; Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany; Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, GermanyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Consorzio Interuniversitario Biotecnologie (CIB), Unit of Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S200103702400076XLipidomicsGalactosylceramidaseKrabbe diseaseMolecular modelingZebrafish |
| spellingShingle | 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 Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos Computational and Structural Biotechnology Journal Lipidomics Galactosylceramidase Krabbe disease Molecular modeling Zebrafish |
| title | Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| title_full | Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| title_fullStr | Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| title_full_unstemmed | Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| title_short | Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| title_sort | impact of an irreversible β galactosylceramidase inhibitor on the lipid profile of zebrafish embryos |
| topic | Lipidomics Galactosylceramidase Krabbe disease Molecular modeling Zebrafish |
| url | http://www.sciencedirect.com/science/article/pii/S200103702400076X |
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