Higher apoptotic state in Fabry disease peripheral blood mononuclear cells.: effect of globotriaosylceramide

Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme α-galactosidase A, resulting in intracellular deposition of globotriaosylceramide (Gb3). Accumulation of Gb3 is probably related to tissue and organ dysfunctions. Diverse pathological mechanisms are elicite...

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Bibliographic Details
Published in:Molecular genetics and metabolism 2011-11, Vol.104 (3), p.319-324
Main Authors: De Francesco, Pablo N, Mucci, Juan M, Ceci, Romina, Fossati, Carlos A, Rozenfeld, Paula A
Format: Article
Language:English
Subjects:
Adolescent
Adult
alpha-Galactosidase
Analysis of Variance
Annexin A5
Apoptosis - drug effects
Apoptosis - physiology
Child
Child, Preschool
Dose-Response Relationship, Drug
Enzyme Replacement Therapy
Fabry Disease - drug therapy
Fabry Disease - physiopathology
Female
Flow Cytometry
Humans
Immunoblotting
In Situ Nick-End Labeling
Isoenzymes
Leukocytes, Mononuclear - metabolism
Leukocytes, Mononuclear - physiology
Male
Middle Aged
Polymerase Chain Reaction
Trihexosylceramides - metabolism
Trihexosylceramides - pharmacology
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Summary:Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme α-galactosidase A, resulting in intracellular deposition of globotriaosylceramide (Gb3). Accumulation of Gb3 is probably related to tissue and organ dysfunctions. Diverse pathological mechanisms are elicited in LSDs, giving together the phenotypic expression of each disease. The purpose of the present study is to investigate if apoptosis could play a role in Fabry disease pathogenesis and to understand the mechanisms involved in the proapoptotic state. We have demonstrated that Fabry disease peripheral blood mononuclear cells display a higher apoptotic state, which is reduced by enzyme replacement therapy (ERT), and is mediated, at least in part, by activation of the intrinsic pathway of caspases. We could rule out the implication of "unfolded protein response-ER stress" in this apoptotic process. To further confirm the suggestion that Gb3 is associated to apoptotic cell death, we treated normal cells with Gb3 at concentrations found in Fabry patients. Addition of Gb3 resulted in a dose-dependent induction of apoptosis involving the intrinsic pathway. In summary, PBMC from Fabry patients display a higher apoptotic state, which could be mainly related to elevated Gb3.
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2011.06.007