Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy
Braun, Fabian; Abed, Ahmed; Sellung, Dominik; Rogg, Manuel; Woidy, Mathias; Eikrem, Øystein Solberg; Wanner, Nicola; Gambardella, Jessica; Laufer, Sandra; Haas, Fabian; Wong, Milagros; Dumoulin, Bernhard; Rischke, Paula; Mühlig, Anne; Sachs, Wiebke; von Cossel, Katharina M; Schulz, Kristina; Muschol, Nicole; Gersting, Sören; Muntau, Ania C.; Kretz, Oliver; Hahn, Oliver; Rinschen, Markus; Mauer, Michael; Bork, Tillmann; Grahammer, Florian; Liang, Wei; Eierhoff, Thorsten; Römer, Winfried; Hansen, Arne; Meyer-Schwesinger, Catherine; Iaccarino, Guido; Tøndel, Camilla; Marti, Hans Peter; Najafian, Behzad; Puelles, Victor G; Schell, Christoph; Huber, Tobias B
Journal article, Peer reviewed
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Date
2023Metadata
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- Department of Clinical Medicine [2124]
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Abstract
Current therapies for Fabry disease are based on reversing intracellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosomal dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease, remains unclear. In this study, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/Cas9–mediated α-galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified α-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.