Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy

Abstract

BackgroundFabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology.MethodsTwo-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry diseaseResultsAfter short-term ERT (4–12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, β-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46–96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients.ConclusionThese results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation.

De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans

“…Western blot was performed according to the previously described methods [ 21 ] with minor modifications. Samples were extracted following homogenization in RIPA buffer, and protein concentrations were determined using a protein assay kit (Bio-Rad, Hercules, California, USA) with BSA as the standard.…”

Biomarkers in Anderson–Fabry Disease

“…Additionally, it was difficult to establish whether iCb3 changes reflect the immune response to enzyme therapy and whether its reduction suggested the stabilization of the complement activity during ERT. These findings suggest that the complement pathway takes part in the pathogenesis of the disease, and ERT reduces further activation of the complement pathway [67].…”

“…Previous studies were conducted to find new biomarkers with several efforts to detect metabolites that may assess the effectiveness of ERT to monitor disease progression. A recent study analyzed plasma proteome profiles before and after ERT in order to better define the molecular pathology of Fabry disease [67].…”

Biomarkers of Fabry Nephropathy: Review and Future Perspective

“…Lyso-Gb3 is a promising biomarker as it is directly involved in the pathogenesis of the disease through the stimulation of inflammation and fibrosis by inducing the release of secondary mediators of glomerular damage in diabetic nephropathy [103,104]. In addition, lyso-Gb3 promotes the proliferation of vascular smooth muscle cells [3] and may be a potential driver of CD80 expression [21], suggesting that these cells act as antigen presentation cells and are involved in inflammatory pathways [105]. Additionally, CD80 interaction with integrins has been associated with podocyte migration, detachment, and podocyturia [21].…”