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

Fabry disease (FD) is caused by mutations in the α-galactosidase A (<i>GLA</i>) 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 increa...

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Autores principales:	Ulrich Jehn, Samet Bayraktar, Solvey Pollmann, Veerle Van Marck, Thomas Weide, Hermann Pavenstädt, Eva Brand, Malte Lenders
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Fabry disease podocytes α-galactosidase A-deficiency proteome analysis sphingolipids Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/70bbf552057440518a268a3f9bfccd02
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spelling	oai:doaj.org-article:70bbf552057440518a268a3f9bfccd022021-11-11T16:49:09Zα-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes10.3390/ijms2221113391422-00671661-6596https://doaj.org/article/70bbf552057440518a268a3f9bfccd022021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11339https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Fabry disease (FD) is caused by mutations in the α-galactosidase A (<i>GLA</i>) 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.Ulrich JehnSamet BayraktarSolvey PollmannVeerle Van MarckThomas WeideHermann PavenstädtEva BrandMalte LendersMDPI AGarticleFabry diseasepodocytesα-galactosidase A-deficiencyproteome analysissphingolipidsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11339, p 11339 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fabry disease podocytes α-galactosidase A-deficiency proteome analysis sphingolipids Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Fabry disease podocytes α-galactosidase A-deficiency proteome analysis sphingolipids Biology (General) QH301-705.5 Chemistry QD1-999 Ulrich Jehn Samet Bayraktar Solvey Pollmann Veerle Van Marck Thomas Weide Hermann Pavenstädt Eva Brand Malte Lenders α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
description	Fabry disease (FD) is caused by mutations in the α-galactosidase A (<i>GLA</i>) 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.
format	article
author	Ulrich Jehn Samet Bayraktar Solvey Pollmann Veerle Van Marck Thomas Weide Hermann Pavenstädt Eva Brand Malte Lenders
author_facet	Ulrich Jehn Samet Bayraktar Solvey Pollmann Veerle Van Marck Thomas Weide Hermann Pavenstädt Eva Brand Malte Lenders
author_sort	Ulrich Jehn
title	α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
title_short	α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
title_full	α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
title_fullStr	α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
title_full_unstemmed	α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes
title_sort	α-galactosidase a deficiency in fabry disease leads to extensive dysregulated cellular signaling pathways in human podocytes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/70bbf552057440518a268a3f9bfccd02
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α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

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