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  - 
TY  - JOUR
A1  - Neugebauer, Ina
A1  - Brauer, Achim
A1  - Draeger, Nadine
A1  - Dulski, Peter
A1  - Wulf, Sabine
A1  - Plessen, Birgit
A1  - Mingram, Jens
A1  - Herzschuh, Ulrike
A1  - Brande, Arthur
T1  - A Younger Dryas varve chronology from the Rehwiese palaeolake record in NE-Germany
JF  - Quaternary science reviews : the international multidisciplinary research and review journal
N2  - The first 1400-year floating varve chronology for north-eastern Germany covering the late Allered to the early Holocene has been established by microscopic varve counts from the Rehwiese palaeolake sediment record. The Laacher See Tephra (LST), at the base of the studied interval, forms the tephrochronological anchor point. The fine laminations were examined using a combination of micro-facies and mu XRF analyses and are typical of calcite varves, which in this case provide mainly a warm season signal. Two varve types with different sub-layer structures have been distinguished: (I) complex varves consisting of up to four seasonal sub-layers formed during the Allered and early Holocene periods, and, (II) simple two sub-layer type varves only occurring during the Younger Dryas. The precision of the chronology has been improved by varve-to-varve comparison of two independently analyzed sediment profiles based on well-defined micro-marker layers. This has enabled both (1) the precise location of single missing varies in one of the sediment profiles, and, (2) the verification of varve interpolation in disturbed varve intervals in the parallel core. Inter-annual and decadal-scale variability in sediment deposition processes were traced by multi-proxy data series including seasonal layer thickness, high-resolution element scans and total organic and inorganic carbon data at a five-varve resolution. These data support the idea of a two-phase Younger Dryas, with the first interval (12,675-12,275 varve years BP) characterised by a still significant but gradually decreasing warm-season calcite precipitation and a second phase (12,275-11,690 varve years BP) with only weak calcite precipitation. Detailed correlation of these two phases with the Meerfelder Maar record based on the LST isochrone and independent varve counts provides clues about regional differences and seasonal aspects of YD climate change along a transect from a location proximal to the North Atlantic in the west to a more continental site in the east
KW  - Varve chronology
KW  - Micro-fades
KW  - Micro-XRF
KW  - Younger Dryas
KW  - North-eastern Germany
Y1  - 2012
U6  - https://doi.org/10.1016/j.quascirev.2011.12.010
SN  - 0277-3791
VL  - 36
IS  - 10
SP  - 91
EP  - 102
PB  - Elsevier
CY  - Oxford
ER  -