Universität zu Köln

Beckmann, Nadine, Kadow, Stephanie, Schumacher, Fabian ORCID: 0000-0001-8703-3275, Goethert, Joachim R., Kesper, Stefanie, Draeger, Annette, Schulz-Schaeffer, Walter J., Wang, Jiang, Becker, Jan U., Kramer, Melanie, Kuehn, Claudine, Kleuser, Burkhard ORCID: 0000-0002-1888-9595, Becker, Katrin Anne, Gulbins, Erich and Carpinteiro, Alexander (2018). Pathological manifestations of Farber disease in a new mouse model. Biol. Chem., 399 (10). S. 1183 - 1203. BERLIN: WALTER DE GRUYTER GMBH. ISSN 1437-4315

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Beckmann, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kadow, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Fabian UNSPECIFIED orcid.org/0000-0001-8703-3275 UNSPECIFIED Goethert, Joachim R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kesper, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Draeger, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz-Schaeffer, Walter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Jiang UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Jan U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kramer, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuehn, Claudine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleuser, Burkhard UNSPECIFIED orcid.org/0000-0002-1888-9595 UNSPECIFIED Becker, Katrin Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Gulbins, Erich UNSPECIFIED UNSPECIFIED UNSPECIFIED Carpinteiro, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-172149
DOI:	10.1515/hsz-2018-0170
Journal or Publication Title:	Biol. Chem.
Volume:	399
Number:	10
Page Range:	S. 1183 - 1203
Date:	2018
Publisher:	WALTER DE GRUYTER GMBH
Place of Publication:	BERLIN
ISSN:	1437-4315
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACID CERAMIDASE DEFICIENCY; SPINAL MUSCULAR-ATROPHY; BONE-MARROW-TRANSPLANTATION; MYOCLONIC EPILEPSY; SPHINGOMYELINASE; ACCUMULATION; MUTATIONS; DIAGNOSIS; CELLS; GENE Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17214