Systemic ceramide accumulation leads to severe and varied pathological consequences

EMBO Molecular Medicine

Abdulfatah M. Alayoubi⁷  James C. M. Wang⁴  Bryan C. Y. Au⁴  Stéphane Carpentier⁶  Virginie Garcia⁶  Shaalee Dworski⁷  Samah El-Ghamrasni⁴  Kevin N. Kirouac⁴  Mathilde J. Exertier⁴  Zi Jian Xiong⁵  Gilbert G. Privé⁴  Calogera M. Simonaro²  Josefina Casas¹  Gemma Fabrias¹  Edward H. Schuchman²  Patricia V. Turner³  Razqallah Hakem⁴  Thierry Levade⁶ 

[1] Research Unit on Bioactive Molecules, Department of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia, Spanish National Research Council, Barcelona, Spain;Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA;Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada;University Health Network, Toronto, Ontario, Canada;Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada;INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, Université Toulouse III Paul-Sabatier, Toulouse, France;Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

关键词: acid ceramidase;    Lysosomal storage disorders;    Farber disease;    MCP‐1;   

DOI  :  10.1002/emmm.201202301

来源: Wiley

【 摘 要 】

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.

→See accompanying article http://dx.doi.org/10.1002/emmm.201302781

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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