Systemic ceramide accumulation leads to severe and varied pathological consequences

97Citations
Citations of this article
73Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Farber disease (FD) is a severe inherited disorder of lipid metabolism characterized by deficient lysosomal acid ceramidase (ACDase) activity, resulting in ceramide accumulation. Ceramide and metabolites have roles in cell apoptosis and proliferation. We introduced a single-nucleotide mutation identified in human FD patients into the murine Asah1 gene to generate the first model of systemic ACDase deficiency. Homozygous Asah1P361R/P361R animals showed ACDase defects, accumulated ceramide, demonstrated FD manifestations and died within 7-13 weeks. Mechanistically, MCP-1 levels were increased and tissues were replete with lipid-laden macrophages. Treatment of neonates with a single injection of human ACDase-encoding lentivector diminished the severity of the disease as highlighted by enhanced growth, decreased ceramide, lessened cellular infiltrations and increased lifespans. This model of ACDase deficiency offers insights into the pathophysiology of FD and the roles of ACDase, ceramide and related sphingolipids in cell signaling and growth, as well as facilitates the development of therapy. © 2013 The Authors.

Cite

CITATION STYLE

APA

Alayoubi, A. M., Wang, J. C. M., Au, B. C. Y., Carpentier, S., Garcia, V., Dworski, S., … Medin, J. A. (2013). Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Molecular Medicine, 5(6), 827–842. https://doi.org/10.1002/emmm.201202301

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free