The Journal of Clinical Investigation (Jun 2023)

Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

  • Fabian Braun,
  • Ahmed Abed,
  • Dominik Sellung,
  • Manuel Rogg,
  • Mathias Woidy,
  • Oysten Eikrem,
  • Nicola Wanner,
  • Jessica Gambardella,
  • Sandra D. Laufer,
  • Fabian Haas,
  • Milagros N. Wong,
  • Bernhard Dumoulin,
  • Paula Rischke,
  • Anne Mühlig,
  • Wiebke Sachs,
  • Katharina von Cossel,
  • Kristina Schulz,
  • Nicole Muschol,
  • Sören W. Gersting,
  • Ania C. Muntau,
  • Oliver Kretz,
  • Oliver Hahn,
  • Markus M. Rinschen,
  • Michael Mauer,
  • Tillmann Bork,
  • Florian Grahammer,
  • Wei Liang,
  • Thorsten Eierhoff,
  • Winfried Römer,
  • Arne Hansen,
  • Catherine Meyer-Schwesinger,
  • Guido Iaccarino,
  • Camilla Tøndel,
  • Hans-Peter Marti,
  • Behzad Najafian,
  • Victor G. Puelles,
  • Christoph Schell,
  • Tobias B. Huber

Journal volume & issue
Vol. 133, no. 11

Abstract

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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.

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