Abstract
Farber disease is an inherited metabolic disorder caused by mutations in the acid ceramidase gene, which leads to ceramide accumulation in lysosomes. Farber disease patients display a wide variety of symptoms with most patients eventually displaying signs of nervous system dysfunction. We now present a novel tool that could potentially be used to distinguish between the milder and more severe forms of the disease, namely, an antibody that recognizes a mixed monolayer or bilayer of cholesterol:C16-ceramide, but does not recognize either ceramide or cholesterol by themselves. This antibody has previously been used to detect cholesterol:C16-ceramide domains in a variety of cultured cells. We demonstrate that levels of cholesterol:C16-ceramide domains are significantly elevated in fibroblasts from types 4 and 7 Farber disease patients, and that levels of the domains can be modulated by either reducing ceramide or cholesterol levels. Moreover, these domains are located in membranes of the endomembrane system, and also in two unexpected locations, namely, the mitochondria and the plasma membrane. This study suggests that the ceramide that accumulates in severe forms of Farber disease cells is sequestered to distinct membrane subdomains, which may explain some of the cellular pathology observed in this devastating lysosomal storage disease.
Competing interests: None declared
Authors Natalia Santos Ferreira and Michal Goldschmidt-Arzi contributed equally to this study
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- CD:
-
2-hydroxypropyl-β-cyclodextrin
- Cer/chol:
-
ceramide/cholesterol
- LSD:
-
lysosomal storage disease
- PBS:
-
phosphate buffered saline
- TEM:
-
transmission electron microscopy
- WT:
-
wild type
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Acknowledgments
N.S. Ferreira is a recipient of a PhD fellowship from the Fundação para a Ciência e Tecnologia (SFRH/BD/40319/2007). Electron microscopy was performed at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute. We thank Dr. Lúcia Lacerda for providing cells and Vladimir Kiss for help with confocal microscopy. A.H. Futerman is the Joseph Meyerhoff Professor of Biochemistry and Lia Addadi is the incumbent of the Dorothy-and-Patrick-Gorman Professorial Chair of Biological Ultrastructure at the Weizmann Institute of Science.
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Communicated by: Gregory M. Pastores, MD
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Ferreira, N.S. et al. (2013). Accumulation of Ordered Ceramide-Cholesterol Domains in Farber Disease Fibroblasts. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 12. JIMD Reports, vol 12. Springer, Cham. https://doi.org/10.1007/8904_2013_246
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DOI: https://doi.org/10.1007/8904_2013_246
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