Open AccessSystemic ceramide accumulation leads to severe and varied pathological consequences
Author(s) -
Alayoubi Abdulfatah M.,
Wang James C. M.,
Au Bryan C. Y.,
Carpentier Stéphane,
Garcia Virginie,
Dworski Shaalee,
ElGhamrasni 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.
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201202301
Subject(s) - ceramide , pathological , chemistry , medicine , microbiology and biotechnology , biology , pathology , apoptosis , biochemistry
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.