Reduced α-galactosidase A activity in zebrafish (Danio rerio) mirrors distinct features of Fabry nephropathy phenotype

Elsaid, Hassan Osman Alhassan; Furriol, Jessica; Blomqvist, Maria; Diswall, Mette; Leh, Sabine; Gharbi, Naouel; Anonsen, Jan Haug; Bábíčková, Janka; Tøndel, Camilla; Svarstad, Einar; Marti, Hanspeter; Krause, Maximilian

doi:10.1016/j.ymgmr.2022.100851

Cited by 10 publications

(21 citation statements)

References 87 publications

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“…Biopsy specimen, however, showed mild interstitial fibrosis and podocytopathy (effacement of podocyte pedicels, and non-membrane bound lipid droplets in proximal tubular epithelium and interstitial cells). Interestingly, pedicel effacement was very similar to Gb3Cerindependent podocyte changes reported in the zebrafish AGAL deficient model [13] thus providing further evidence for lysosomal storage independent mechanism of FD pathogenesis.…”

Section: Discussionsupporting

confidence: 73%

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AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Methods We characterized the clinical, biochemical, genetic, molecular, cellular and organ pathology correlates of the p.L394P AGAL variant that was identified in six individuals with end-stage kidney disease by the Czech national screening program for FD and by further screening of 25 family members. Results Clinical findings revealed a milder clinical course with ~15% residual AGAL activity. Laboratory investigations documented intracellular retention of mutated AGAL with resulting ER stress and the unfolded protein response (UPR). Kidney biopsies did not show lysosomal storage. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense GLA variants. Conclusions We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms.

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Section: Discussionsupporting

confidence: 73%

“…While the pathogenesis of FD has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal Gb3Cer accumulation and impairment of lysosomal functions [12], other factors may also contribute [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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“…In the attempt to overcome such limitations, murine and zebrafish models of Fabry’s disease have been generated. Murine models, however, do not fully recapitulate FD phenotype and mice, even if showing kidney and cardiac GB3 accumulations, have a normal lifetime ( 16 , 17 ). On the other hand, zebrafish cannot accumulate GB3 lacking GB3 synthase and the GLA gene is on an autosomal chromosome ( 16 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Murine models, however, do not fully recapitulate FD phenotype and mice, even if showing kidney and cardiac GB3 accumulations, have a normal lifetime ( 16 , 17 ). On the other hand, zebrafish cannot accumulate GB3 lacking GB3 synthase and the GLA gene is on an autosomal chromosome ( 16 , 17 ). However, this model has the advantage of the short growing rate and time to observe the effects of the disease in the kidney ( 16 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Sansone,

Barreca,

Belli

et al. 2024

Front. Endocrinol.

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IntroductionFabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease characterized by the accumulation of globotriaosylceramide (GB3) into the lysosomes of many tissues. FD is due to loss-of-function mutations of α-galactosidase, a key-enzyme for lysosomal catabolism of glycosphingolipids, which accumulate as glycolipid bodies (GB). In homozygous males the progressive deposition of GB3 into the cells leads to clinical symptoms in CNS, skin, kidney, etc. In testis GB accumulation causes infertility and alterations of spermatogenesis. However, the precise damaging mechanism is still unknown. Our hypothesis is that GB accumulation reduces blood vessel lumen and increases the distance of vessels from both stromal cells and seminiferous parenchyma; this, in turn, impairs oxygen and nutrients diffusion leading to subcellular degradation of seminiferous epithelium and sterility.MethodsTo test this hypothesis, we have studied a 42-year-old patient presenting a severe FD and infertility, with reduced number of spermatozoa, but preserved sexual activity. Testicular biopsies were analyzed by optical (OM) and transmission electron microscopy (TEM). Activation and cellular localization of HIF-1α and NFκB was analyzed by immunofluorescence (IF) and RT-PCR on homogeneous tissue fractions after laser capture microdissection (LCMD).ResultsOM and TEM showed that GB were abundant in vessel wall cells and in interstitial cells. By contrast, GB were absent in seminiferous epithelium, Sertoli’s and Leydig’s cells. However, seminiferous tubular epithelium and Sertoli’s cells showed reduced diameter, thickening of basement membrane and tunica propria, and swollen or degenerated spermatogonia. IF showed an accumulation of HIF-1α in stromal cells but not in seminiferous tubules. On the contrary, NFκB fluorescence was evident in tubules, but very low in interstitial cells. Finally, RT-PCR analysis on LCMD fractions showed the expression of pro-inflammatory genes connected to the HIF-1α/NFκB inflammatory-like pathway.ConclusionOur study demonstrates that infertility in FD may be caused by reduced oxygen and nutrients due to GB accumulation in blood vessels cells. Reduced oxygen and nutrients alter HIF-1α/NFκB expression and localization while activating HIF-1α/NFκB driven-inflammation-like response damaging seminiferous tubular epithelium and Sertoli’s cells.

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“…However, these models also have limitation to represent complex cell types comprising the kidney. Recently, zebrafish were found to mimic human FDN in inducing GLA mutation that lead to reduced α-GalA activity [ 8 ]. However, the pathogenesis of FDN in zebra fish is different to that in humans, because Gb-3 synthase is absent in zebrafish, so deposits of Gb-3 are not involved in FDN development.…”

Section: Introductionmentioning

confidence: 99%

Modeling of Fabry disease nephropathy using patient derived human induced pluripotent stem cells and kidney organoid system

et al. 2023

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Objectives To explore the possibility of kidney organoids generated using patient derived human induced pluripotent stem cells (hiPSC) for modeling of Fabry disease nephropathy (FDN). Methods First, we generated hiPSC line using peripheral blood mononuclear cells (PBMCs) from two male FD-patients with different types of GLA mutation: a classic type mutation (CMC-Fb-001) and a non-classic type (CMC-Fb-003) mutation. Second, we generated kidney organoids using wild-type (WT) hiPSC (WTC-11) and mutant hiPSCs (CMC-Fb-001 and CMC-Fb-003). We then compared alpha-galactosidase A (α-GalA) activity, deposition of globotriaosylceremide (Gb-3), and zebra body formation under electromicroscopy (EM). Results Both FD patients derived hiPSCs had the same mutations as those detected in PBMCs of patients, showing typical pluripotency markers, normal karyotyping, and successful tri-lineage differentiation. Kidney organoids generated using WT-hiPSC and both FD patients derived hiPSCs expressed typical nephron markers without structural deformity. Activity of α-GalA was decreased and deposition of Gb-3 was increased in FD patients derived hiPSCs and kidney organoids in comparison with WT, with such changes being far more significant in CMC-Fb-001 than in CMC-Fb-003. In EM finding, multi-lammelated inclusion body was detected in both CMC-Fb-001 and CMC-Fb-003 kidney organoids, but not in WT. Conclusions Kidney organoids generated using hiPSCs from male FD patients might recapitulate the disease phenotype and represent the severity of FD according to the GLA mutation type.

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Reduced α-galactosidase A activity in zebrafish (Danio rerio) mirrors distinct features of Fabry nephropathy phenotype

Cited by 10 publications

References 87 publications

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Modeling of Fabry disease nephropathy using patient derived human induced pluripotent stem cells and kidney organoid system

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