EMBO molecular medicine · 2013
Systemic ceramide accumulation leads to severe and varied pathological consequences.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Alayoubi Abdulfatah M, Wang James C M, Au Bryan C Y, Carpentier Stéphane, Garcia Virginie, Dworski Shaalee, El-Ghamrasni Samah, Kirouac Kevin N, Exertier Mathilde J, Xiong Zi Jian, Privé Gilbert G, Simonaro Calogera M, Casas Josefina, Fabrias Gemma, Schuchman Edward H, Turner Patricia V, Hakem Razqallah, Levade Thierry, Medin Jeffrey A
Аннотация
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.