Systemic ceramide accumulation leads to severe and varied pathological consequences.

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 Asah1(P361R/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.

• Authors: Abdulfatah M Alayoubi, James C M Wang, Bryan C Y Au, Stéphane Carpentier, Virginie Garcia, Shaalee Dworski, Samah El-Ghamrasni, Kevin N Kirouac, Mathilde J Exertier, Zi Jian Xiong, Gilbert G Privé, Calogera M Simonaro, Josefina Casas, Gemma Fabrias, Edward H Schuchman, Patricia V Turner, Razqallah Hakem, Thierry Levade, Jeffrey A Medin
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 6 Pg. 827-42 (Jun 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23681708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• Ccl2 protein, mouse
• Ceramides
• Chemokine CCL2
• Acid Ceramidase
• Asah1 protein, mouse

Topics

• Acid Ceramidase (genetics, metabolism)
• Animals
• Cells, Cultured
• Ceramides (metabolism)
• Chemokine CCL2 (metabolism)
• Disease Models, Animal
• Embryonic Stem Cells (cytology, metabolism)
• Farber Lipogranulomatosis (genetics, metabolism, pathology)
• Female
• Gene Knock-In Techniques
• Genetic Vectors (genetics, metabolism)
• Homozygote
• Humans
• Lentivirus (genetics)
• Macrophages (immunology, physiology)
• Mice
• Mutation
• Phenotype