Higher apoptotic state in Fabry disease peripheral blood mononuclear cells.

Francesco, Pablo N. De; Mucci, Juan Marcos; Ceci, Romina; Fossati, Carlos A.; Rozenfeld, Paula

doi:10.1016/j.ymgme.2011.06.007

Cited by 30 publications

(17 citation statements)

References 27 publications

(32 reference statements)

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“…Consistent with data indicating that cells from human patients suffering from GD and FD are more susceptible to apoptosis (De Francesco, Mucci, Ceci, Fossati, & Rozenfeld, ; Wei et al, ; Yoo & Kim, ), we demonstrated that GBA and GLA deficiency determined a significantly increased percentage of apoptotic cells in both stem cell cultures (Fig. A).…”

Section: Discussionsupporting

confidence: 91%

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha‐galactosidase A (GLA) enzymes

Squillaro

Antonucci

Alessio

et al. 2017

Journal Cellular Physiology

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Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1 hr after oxidative stress induction and a return to basal level at 48 hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity.

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Section: Discussionsupporting

confidence: 91%

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha‐galactosidase A (GLA) enzymes

Squillaro

Antonucci

Alessio

et al. 2017

Journal Cellular Physiology

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“…However, a greater apoptotic state has been observed in PBMC from Fabry patients (40,43), Gb3-induced apoptosis via TGF-β1 and VEGF overexpression may be associated with Fabry nephropathy.…”

Section: Discussionmentioning

confidence: 97%

“…Activity of caspase-3/7 in the kidney did not differ significantly between Fabry and wild-type mice but was lower in ERT-treated Fabry mice compared with Fabry mice. De Francesco et al (40) suggested that peripheral blood mononuclear cells (PBMC) from Fabry disease’s patients were in an apoptotic state, which correlated with the accumulation of Gb3. This suggests that Fabry nephropathy is associated at least partly with the intrinsic apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

Possible role of transforming growth factor-β1 and vascular endothelial growth factor in Fabry disease nephropathy

Lee

Choi

Jeon

et al. 2012

International Journal of Molecular Medicine

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Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of α-galactosidase A (α-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-β1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-β1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis.

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“…This pathological mechanism would be accessible to chaperone therapy, in which "chaperone" molecules bind to the inactive or unstable misfolded enzymes switching them into a functional shape (Boyd et al 2013). Surprisingly, a study comparing 32 Fabry patients with 30 healthy controls showed that Fabry PBMCs displayed rather a mitochondrial than ER apoptotic pathway (De Francesco et al 2011). This phenomenon could be explained by the different types of mutations (nonsense and mis- sense) in patients, which can lead to very different tertiary structure of proteins and then involve radically different ER stress behaviours.…”

Section: Introductionmentioning

confidence: 99%

Innate and Adaptive Immune Response in Fabry Disease

et al. 2015

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Fabry disease is an X-linked lysosomal storage disease in which mutations of the gene (GLA) cause a deficiency of the lysosomal hydrolase α-galactosidase A (α-Gal). This defect results in an accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) which causes a multisystemic vasculopathy. Available since 2001 in Europe, enzyme replacement therapy consists in the administration of agalsidase, a recombinant form of α-galactosidase A. Enzyme replacement therapy was shown to improve the global prognosis but allowed partial success in preventing critical events such as strokes and cardiac arrests. As in most lysosomal storage diseases, frequent immune reactions have been described in naive Fabry disease patients. Humoral immune responses following enzyme replacement therapy have also been described, with unclear consequences on the progression of the disease. While cost-effectiveness of enzyme replacement therapy in Fabry disease begins to be questioned and new therapeutic strategies arise such as chaperone or gene therapy, it appears necessary to better understand the immune responses observed in the treatment of naive patients and during enzyme replacement therapy with agalsidase. We propose a comprehensive review of the available literature concerning both innate and adaptive responses observed in Fabry disease. We particularly highlight the probable role of the toll-like receptor 4 (TLR4) and CD1d pathways triggered by Gb3 accumulation in the development of local and systemic inflammation that could lead to irreversible organ damages. We propose an immunological point of view of Fabry disease pathogenesis involving immune cells notably the invariant natural killer T cells. We finally review anti-agalsidase antibodies, their development and impact on outcomes.

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Higher apoptotic state in Fabry disease peripheral blood mononuclear cells.

Cited by 30 publications

References 27 publications

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha‐galactosidase A (GLA) enzymes

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha‐galactosidase A (GLA) enzymes

Possible role of transforming growth factor-β1 and vascular endothelial growth factor in Fabry disease nephropathy

Innate and Adaptive Immune Response in Fabry Disease

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