Systemic ceramide accumulation leads to severe and varied pathological consequences
| Autor: | Stéphane Carpentier, Virginie Garcia, Bryan Au, Josefina Casas, Thierry Levade, Razqallah Hakem, James C.M. Wang, Gemma Fabriàs, Kevin N. Kirouac, Calogera M. Simonaro, Patricia V. Turner, Mathilde J. Exertier, Zi Jian Xiong, Samah El‐Ghamrasni, Jeffrey A. Medin, Abdulfatah Alayoubi, Edward H. Schuchman, Gilbert G. Privé, Shaalee Dworski |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Ceramide
Genetic Vectors Closeups Biology Ceramides Lysosomal storage disorders Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Gene Knock-In Techniques ceramide Cells Cultured Chemokine CCL2 Embryonic Stem Cells Research Articles 030304 developmental biology Farber disease 0303 health sciences Macrophages Homozygote Lentivirus acid ceramidase Lipid metabolism medicine.disease Sphingolipid Pathophysiology 3. Good health Acid Ceramidase Disease Models Animal Phenotype Farber Lipogranulomatosis lysosomal storage disease chemistry Apoptosis 030220 oncology & carcinogenesis Mutation Immunology ASAH1 Cancer research Molecular Medicine Female MCP-1 |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | 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. →See accompanying article http://dx.doi.org/10.1002/emmm.201302781 |
| Databáze: | OpenAIRE |
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