Pathological manifestations of Farber disease in a new mouse model.

Beckmann, Nadine; Kadow, Stephanie; Schumacher, Fabian; Göthert, Joachim R; Kesper, Stefanie; Draeger, Annette; Schulz-Schaeffer, Walter J; Wang, Jiang; Becker, Jan U; Kramer, Melanie; Kühn, Claudine; Kleuser, Burkhard; Becker, Katrin Anne; Gulbins, Erich; Carpinteiro, Alexander (2018). Pathological manifestations of Farber disease in a new mouse model. Biological chemistry, 399(10), pp. 1183-1202. De Gruyter 10.1515/hsz-2018-0170

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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. Asah1tmEx1 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Draeger, Annette

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1431-6730

Publisher:

De Gruyter

Language:

English

Submitter:

Annette Draeger

Date Deposited:

20 Feb 2019 10:44

Last Modified:

23 Oct 2019 05:03

Publisher DOI:

10.1515/hsz-2018-0170

PubMed ID:

29908121

Uncontrolled Keywords:

Farber disease acid ceramidase ceramide lysosomal storage disorders

BORIS DOI:

10.7892/boris.125162

URI:

https://boris.unibe.ch/id/eprint/125162

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