title: Higher apoptotic state in Fabry disease peripheral blood mononuclear cells.: effect of globotriaosylceramide.
abstract: 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.
authors: LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata (1900), Argentina.
authors: Pablo N
authors: PN
authors: De Francesco
authors: Juan M
authors: JM
authors: Mucci
authors: Romina
authors: R
authors: Ceci
authors: Carlos A
authors: CA
authors: Fossati
authors: Paula A
authors: PA
authors: Rozenfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D014281:Trihexosylceramides / Q000378:metabolism* / Q000494:pharmacology; D000519:alpha-Galactosidase
chemical_list: D017304:Annexin A5; D007527:Isoenzymes; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase