Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling

Braun, Fabian; Blomberg, Linda; Brodesser, Susanne; Liebau, Max C.; Schermer, Bernhard; Benzing, Thomas; Kurschat, Christine

doi:10.33594/000000077

Cited by 34 publications

(21 citation statements)

References 37 publications

(42 reference statements)

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“…Thus, initiating therapy prior to irreversible cellular impairment is crucial for mitigating damage caused by Gb3 deposition [ 51 ]. As a matter of fact, supplementing GLA activity in order to improve Gb3 clearance was not sufficient to rescue profibrotic signaling and dysregulated autophagy in a podocyte culture model of AFD [ 52 , 53 ]. The use of lyso-Gb3 as a biomarker of AFD and for monitoring of ERT outcome needs to be better investigated since additional mechanisms besides Gb3 accumulation may be taking place in AFD [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson–Fabry disease

Salamon

Biagini²,

Kunderfranco

et al. 2021

Cell Death Dis

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Enzyme replacement therapy (ERT) is a mainstay of treatment for Anderson–Fabry disease (AFD), a pathology with negative effects on the heart and kidneys. However, no reliable biomarkers are available to monitor its efficacy. Therefore, we tested a panel of four microRNAs linked with cardiac and renal damage in order to identify a novel biomarker associated with AFD and modulated by ERT. To this end, 60 patients with a definite diagnosis of AFD and on chronic ERT, and 29 age- and sex-matched healthy individuals, were enrolled by two Italian university hospitals. Only miR-184 met both conditions: its level discriminated untreated AFD patients from healthy individuals (c-statistic = 0.7522), and it was upregulated upon ERT (P < 0.001). On multivariable analysis, miR-184 was independently and inversely associated with a higher risk of cardiac damage (odds ratio = 0.86; 95% confidence interval [CI] = 0.76–0.98; P = 0.026). Adding miR-184 to a comprehensive clinical model improved the prediction of cardiac damage in terms of global model fit, calibration, discrimination, and classification accuracy (continuous net reclassification improvement = 0.917, P < 0.001; integrated discrimination improvement [IDI] = 0.105, P = 0.017; relative IDI = 0.221, 95% CI = 0.002–0.356). Thus, miR-184 is a circulating biomarker of AFD that changes after ERT. Assessment of its level in plasma could be clinically valuable in improving the prediction of cardiac damage in AFD patients.

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Section: Discussionmentioning

confidence: 99%

Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson–Fabry disease

Salamon

Biagini²,

Kunderfranco

et al. 2021

Cell Death Dis

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“…FD is treatable with recombinant enzyme replacement therapy (ERT) since 2001 and chaperone therapy (Migalastat, Amicus) since May 2016. FD-specific treatment may result in a Gb 3 clearance of podocytes in vitro [ 8 ] and in vivo [ 9 ]. However, although short-term treatment over 3 days with ERT confirms a reduction of Gb 3 content in podocytes in vitro, disturbed molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling are not positively affected [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…FD-specific treatment may result in a Gb 3 clearance of podocytes in vitro [ 8 ] and in vivo [ 9 ]. However, although short-term treatment over 3 days with ERT confirms a reduction of Gb 3 content in podocytes in vitro, disturbed molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling are not positively affected [ 8 ]. A major limitation of these cell-based studies is that AGAL activity in podocytes was only transiently and thus not fully inhibited by shRNA [ 8 ], and that wild-type podocytes were treated with pathologic lyso-Gb 3 concentrations [ 7 ] only, not representing a real FD-typical pathological situation, based on genomic alterations (i.e., missense and nonsense mutations) in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…However, although short-term treatment over 3 days with ERT confirms a reduction of Gb 3 content in podocytes in vitro, disturbed molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling are not positively affected [ 8 ]. A major limitation of these cell-based studies is that AGAL activity in podocytes was only transiently and thus not fully inhibited by shRNA [ 8 ], and that wild-type podocytes were treated with pathologic lyso-Gb 3 concentrations [ 7 ] only, not representing a real FD-typical pathological situation, based on genomic alterations (i.e., missense and nonsense mutations) in vivo. To overcome this drawback, we generated a stable AGAL-knockout FD podocyte cell line using an established CRISPR/Cas9-mediated approach [ 10 , 11 ] and performed comprehensive proteomic analyses to identify potential altered pathways.…”

Section: Introductionmentioning

confidence: 99%

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α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

Jehn

Bayraktar

Pollmann

et al. 2021

IJMS

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Fabry disease (FD) is caused by mutations in the α-galactosidase A (GLA) gene encoding the lysosomal AGAL enzyme. Loss of enzymatic AGAL activity and cellular accumulation of sphingolipids (mainly globotriaosylcermide) may lead to podocyturia and renal loss of function with increased cardiovascular morbidity and mortality in affected patients. To identify dysregulated cellular pathways in FD, we established a stable AGAL-deficient podocyte cell line to perform a comprehensive proteome analysis. Imbalanced protein expression and function were analyzed in additional FD cell lines including endothelial, epithelial kidney, patient-derived urinary cells and kidney biopsies. AGAL-deficient podocytes showed dysregulated proteins involved in thermogenesis, lysosomal trafficking and function, metabolic activity, cell-cell interactions and cell cycle. Proteins associated with neurological diseases were upregulated in AGAL-deficient podocytes. Rescues with inducible AGAL expression only partially normalized protein expression. A disturbed protein expression was confirmed in endothelial, epithelial and patient-specific cells, pointing toward fundamental pathway disturbances rather than to cell type-specific alterations in FD. We conclude that a loss of AGAL function results in profound changes of cellular pathways, which are ubiquitously in different cell types. Due to these profound alterations, current approved FD-specific therapies may not be sufficient to completely reverse all dysregulated pathways.

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“…Autophagic flux is impaired in FD possibly due to defective autophagosome maturation (Figure 2), as evident from accumulation of autophagosomes, lysosomes and autophagy substrates in patient fibroblasts, human podocyte model and α-Gal A deficient mice (Chevrier et al, 2010; Liebau et al, 2013; Nelson et al, 2014). However, build-up of autophagosomes may also occur due to increased biogenesis because FD podocytes displayed inhibition of mTOR and increased expression of autophagy initiation genes, BECN1 and GABARAP (Liebau et al, 2013; Braun et al, 2019). Autophagy dysfunction has been suggested to contribute to the neuropathological manifestations of FD, and also to podocyte damage in the kidneys resulting in end-stage renal disease that is a common cause of death in FD (Liebau et al, 2013; Nelson et al, 2014).…”

Section: The Role Of Autophagy In Lipid Storage Disordersmentioning

confidence: 99%

Biomedical Implications of Autophagy in Macromolecule Storage Disorders

Palhegyi

Seranova

Dimova

et al. 2019

Front. Cell Dev. Biol.

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An imbalance between the production and clearance of macromolecules such as proteins, lipids and carbohydrates can lead to a category of diseases broadly known as macromolecule storage disorders. These include, but not limited to, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease associated with accumulation of aggregation-prone proteins, Lafora and Pompe disease associated with glycogen accumulation, whilst lipid accumulation is characteristic to Niemann-Pick disease and Gaucher disease. One of the underlying factors contributing to the build-up of macromolecules in these storage disorders is the intracellular degradation pathway called autophagy. This process is the primary clearance route for unwanted macromolecules, either via bulk non-selective degradation, or selectively via aggrephagy, glycophagy and lipophagy. Since autophagy plays a vital role in maintaining cellular homeostasis, cell viability and human health, malfunction of this process could be detrimental. Indeed, defective autophagy has been reported in a number of macromolecule storage disorders where autophagy is impaired at distinct stages, such as at the level of autophagosome formation, autophagosome maturation or improper lysosomal degradation of the autophagic cargo. Of biomedical relevance, autophagy is regulated by multiple signaling pathways that are amenable to chemical perturbations by small molecules. Induction of autophagy has been shown to improve cell viability and exert beneficial effects in experimental models of various macromolecule storage disorders where the lysosomal functionality is not overtly compromised. In this review, we will discuss the role of autophagy in certain macromolecule storage disorders and highlight the potential therapeutic benefits of autophagy enhancers in these pathological conditions.

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Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 34 publications

References 37 publications

Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson–Fabry disease

Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson–Fabry disease

α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

Biomedical Implications of Autophagy in Macromolecule Storage Disorders

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