Accumulation of ordered ceramide-cholesterol domains in farber disease fibroblasts

Natalia Santos Ferreira, Michal Goldschmidt-Arzi, Helena Sabanay, Judith Storch, Thierry Levade, Maria Gil Ribeiro, Lia Addadi, Anthony H. Futerman

Research output: Chapter in Book/Report/Conference proceedingChapter

11 Scopus citations

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.

Original languageEnglish (US)
Title of host publicationJIMD Reports
PublisherSpringer
Pages71-77
Number of pages7
DOIs
StatePublished - 2014

Publication series

NameJIMD Reports
Volume12
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Keywords

  • Cholesterol depletion
  • Endomembrane system
  • Late endosome
  • Lysosomal storage disease
  • Mixed monolayer

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