Nadine Beckmann, Stephanie Kadow, Fabian Schumacher, Joachim R. Goethert, Stefanie Kesper, Annette Draeger, Walter J. Schulz-Schaeffer, Jiang Wang, Jan U. Becker, Melanie Kramer, Claudine Kuehn, Burkhard Kleuser, Katrin Anne Becker, Erich Gulbins, Alexander Carpinteiro
- Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. HistiocyticFarber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.…
MetadatenVerfasserangaben: | Nadine Beckmann, Stephanie Kadow, Fabian SchumacherORCiDGND, Joachim R. Goethert, Stefanie Kesper, Annette Draeger, Walter J. Schulz-Schaeffer, Jiang Wang, Jan U. Becker, Melanie Kramer, Claudine Kuehn, Burkhard KleuserORCiDGND, Katrin Anne Becker, Erich GulbinsORCiDGND, Alexander Carpinteiro |
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DOI: | https://doi.org/10.1515/hsz-2018-0170 |
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ISSN: | 1431-6730 |
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ISSN: | 1437-4315 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/29908121 |
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Titel des übergeordneten Werks (Englisch): | Biological chemistry |
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Verlag: | De Gruyter |
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Verlagsort: | Berlin |
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Publikationstyp: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Datum der Erstveröffentlichung: | 25.09.2018 |
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Erscheinungsjahr: | 2018 |
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Datum der Freischaltung: | 22.09.2021 |
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Freies Schlagwort / Tag: | Farber disease; acid ceramidase; ceramide; lysosomal storage disorders |
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Band: | 399 |
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Ausgabe: | 10 |
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Seitenanzahl: | 20 |
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Erste Seite: | 1183 |
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Letzte Seite: | 1202 |
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Fördernde Institution: | DFGGerman Research Foundation (DFG) [GU 335-35/1, GRK 2098] |
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Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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| Humanwissenschaftliche Fakultät / Strukturbereich Kognitionswissenschaften / Department Sport- und Gesundheitswissenschaften |
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DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Peer Review: | Referiert |
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Publikationsweg: | Open Access / Green Open-Access |
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