Alteration of proteomic profiles in PBMC isolated from patients with Fabry disease: preliminary findings

Abstract

Fabry disease (FD) is an X-linked progressive multisystem disease due to mutations in the gene encoding the lysosomal enzyme α-galactosidase A (α-GalA). The deficiency in α-GalA activity leads to an intra-lysosomal accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3), in various organs and systems. Enzyme replacement therapy is available and alternative therapeutic approaches are being explored. No diagnostic test, other than sequencing of the α-galactosidase A gene, is available, no biomarker has been proven useful to screen for and predict the disease, and underlying mechanisms are still elusive. The aim of this study is to identify FD specific biomarkers and to better understand the pathophysiological changes that occur over time in FD. We compared peripheral blood mononuclear cells (PBMC) from FD patients (n = 8) with control PBMC from healthy individuals (n = 6), by two-dimensional electrophoresis (2DE) and the detected differentially expressed proteins were then subjected to matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). In FD patients we identified, among the down-regulated proteins, Calnexin, Rho GDP-dissociation inhibitor 2, Rho GDP-dissociation inhibitor 1, Chloride intracellular channel protein 1; on the other hand γ-enolase, 14-3-3 protein theta, 14-3-3 protein zeta/delta, and galectin-1 were identified as up-regulated proteins. Calnexin and Rho GDP-dissociation inhibitor-1,2 are related to protein folding, signal transduction and cell proliferation. This is the first time that γ-enolase and galectin-1 are described to be up-regulated in Fabry patients. Levels of γ-enolase increase dramatically in cardiovascular accidents and cerebral trauma, whereas galectins are regulators of acute and chronic inflammation. These findings may improve our understanding of the molecular mechanisms underlying the pathology and provide new insight and knowledge for future studies in this field.

Cerebrovascular Involvement in Fabry Disease

“…γ-enolase increases significantly in cerebrovascular accidents and in brain trauma, and galectins are involved in the regulation of inflammation. 118 GL-3 concentrations, although elevated in plasma and urine of male Fabry patients, may be normal in heterozygous female Fabry patients and do not correlate with clinical symptoms 119 or serve as a predictor of disease progression or outcome after enzyme replacement therapy. 120 With the discovery of high levels of lyso-GL-3 in plasma from patients with FD, 5 it was anticipated that this deacylated form of GL-3 might serve as a reliable biomarker of FD.…”

Gender‐specific plasma proteomic biomarkers in patients with Anderson–Fabry disease

“…Proteomic analyses, meanwhile, offer a potential complement to metabolomic analyses, which, in concert, may generate a more complete picture of the pathophysiology of AFD . In comparing our results with proteomic analysis in peripheral blood mononuclear cells (PBMCs), similar themes emerge, whereby cell signalling molecules are altered . Furthermore, the AFD proteome in PBMCs implicates inflammation, whereas our data implicate oxidative stress, which implies that these processes are dysregulated in tandem.…”

Biomarkers and Imaging Findings of Anderson–Fabry Disease—What We Know Now

“…All proteins that were found to have significant expression differences (either up or down regulation) play a role in the mechanisms that may be associated with the pathophysiology of the AFD [53]. …”