Synuclein alpha accumulation mediates podocyte injury in Fabry nephropathy

Abstract

Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosome dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease remains unclear. First, 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 alpha-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 alpha-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.

Integrating basic science with translational research: the 13th International Podocyte Conference 2021

“…Although accumulation of globotriaosylceramide in lysosomes has been considered the major pathologic factor in Fabry disease, 85 Fabian Braun illustrated a globotriaosylceramide-independent accumulation of pathogenic synuclein α in Fabry podocytes. 86 Finally, Fabiola Terzi investigated the effect of aging on glomerular signaling and showed that aging-associated signaling from PAI-1–positive senescent endothelial cells contributes to podocyte loss and glomerular scarring. 87 Both PAI-1 inhibition and senolysis rescued podocyte numbers in aging mice, and PAI-1 expression was found as a predictor of kidney transplant survival.…”