TY  - JOUR
A1  - Beckmann, Nadine
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Goethert, Joachim R.
A1  - Kesper, Stefanie
A1  - Draeger, Annette
A1  - Schulz-Schaeffer, Walter J.
A1  - Wang, Jiang
A1  - Becker, Jan U.
A1  - Kramer, Melanie
A1  - Kuehn, Claudine
A1  - Kleuser, Burkhard
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Pathological manifestations of Farber disease in a new mouse model
JF  - Biological chemistry
N2  - 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. 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.
KW  - acid ceramidase
KW  - ceramide
KW  - Farber disease
KW  - lysosomal storage disorders
Y1  - 2018
U6  - https://doi.org/10.1515/hsz-2018-0170
SN  - 1431-6730
SN  - 1437-4315
VL  - 399
IS  - 10
SP  - 1183
EP  - 1202
PB  - De Gruyter
CY  - Berlin
ER  -