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:
CreatorsEmailORCIDORCID Put Code
Beckmann, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kadow, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, FabianUNSPECIFIEDorcid.org/0000-0001-8703-3275UNSPECIFIED
Goethert, Joachim R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kesper, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Draeger, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz-Schaeffer, Walter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, JiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Jan U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramer, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehn, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleuser, BurkhardUNSPECIFIEDorcid.org/0000-0002-1888-9595UNSPECIFIED
Becker, Katrin AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gulbins, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carpinteiro, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
ACID CERAMIDASE DEFICIENCY; SPINAL MUSCULAR-ATROPHY; BONE-MARROW-TRANSPLANTATION; MYOCLONIC EPILEPSY; SPHINGOMYELINASE; ACCUMULATION; MUTATIONS; DIAGNOSIS; CELLS; GENEMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17214

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