title: 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.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abdulfatah M
authors.initials: AM
authors.lastname: Alayoubi
authors.forename: James C M
authors.initials: JC
authors.lastname: Wang
authors.forename: Bryan C Y
authors.initials: BC
authors.lastname: Au
authors.forename: Stéphane
authors.initials: S
authors.lastname: Carpentier
authors.forename: Virginie
authors.initials: V
authors.lastname: Garcia
authors.forename: Shaalee
authors.initials: S
authors.lastname: Dworski
authors.forename: Samah
authors.initials: S
authors.lastname: El-Ghamrasni
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Kirouac
authors.forename: Mathilde J
authors.initials: MJ
authors.lastname: Exertier
authors.forename: Zi Jian
authors.initials: ZJ
authors.lastname: Xiong
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Privé
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabrias
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Turner
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D055577:Farber Lipogranulomatosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055879:Gene Knock-In Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D009154:Mutation; D010641:Phenotype
chemical_list: C491768:Ccl2 protein, mouse; D002518:Ceramides; D018932:Chemokine CCL2; D055573:Acid Ceramidase; C526734:Asah1 protein, mouse