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.
Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy / Braun, F.; Abed, A.; Sellung, D.; Rogg, M.; Woidy, M.; Eikrem, O.; Wanner, N.; Gambardella, J.; Laufer, S. D.; Haas, F.; Wong, M. N.; Dumoulin, B.; Rischke, P.; Muhlig, A.; Sachs, W.; von Cossel, K.; Schulz, K.; Muschol, N.; Gersting, S. W.; Muntau, A. C.; Kretz, O.; Hahn, O.; Rinschen, M. M.; Mauer, M.; Bork, T.; Grahammer, F.; Liang, W.; Eierhoff, T.; Romer, W.; Hansen, A.; Meyer-Schwesinger, C.; Iaccarino, G.; Tondel, C.; Marti, H. -P.; Najafian, B.; Puelles, V. G.; Schell, C.; Huber, T. B.. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 133:11(2023). [10.1172/JCI157782]
Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy
Gambardella J.Investigation
;Iaccarino G.Conceptualization
;
2023
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
