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

DE FRANCESCO, PN; MUCCI J; CECI R; FOSSATI CA; ROZENFELD PA

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2011 vol. 104 p. 319 - 324

1096-7192

Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme α-galactosidaseA, resulting in intracellular deposition of globotriaosylceramide (Gb3). Accumulation of Gb3 is probablyrelated to tissue and organ dysfunctions. Diverse pathological mechanisms are elicited in LSDs, givingtogether the phenotypic expression of each disease. The purpose of the present study is to investigate ifapoptosis could play a role in Fabry disease pathogenesis and to understand the mechanisms involved in theproapoptotic state. We have demonstrated that Fabry disease peripheral blood mononuclear cells display ahigher apoptotic state, which is reduced by enzyme replacement therapy (ERT), and is mediated, at least inpart, by activation of the intrinsic pathway of caspases. We could rule out the implication of “unfolded proteinresponse-ER stress” in this apoptotic process. To further confirm the suggestion that Gb3 is associated toapoptotic cell death, we treated normal cells with Gb3 at concentrations found in Fabry patients. Addition ofGb3 resulted in a dose-dependent induction of apoptosis involving the intrinsic pathway. In summary, PBMCfrom Fabry patients display a higher apoptotic state, which could be mainly related to elevated Gb3.