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Abstract: FR-PO699

Synuclein Alpha Accumulation Mediates Podocyte Injury in Fabry Nephropathy

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology


  • Braun, Fabian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Abed, Ahmed, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Eikrem, Oystein, Universitetet i Bergen Det medisinsk-odontologiske fakultet, Bergen, Norway
  • Wanner, Nicola, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Gersting, Soeren W., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Muntau, Ania C., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Kretz, Oliver, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Najafian, Behzad, University of Washington, Seattle, Washington, United States
  • Tøndel, Camilla, Haukeland Universitetssjukehus, Bergen, Norway
  • Mauer, Michael, University of Minnesota, Minnesota, Minnesota, United States
  • Bork, Tillmann, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Grahammer, Florian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Eierhoff, Thorsten, University Hospital Münster, Münster, Nordrhein-Westfalen, Germany
  • Römer, Winfried, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Marti, Hans-Peter, Universitetet i Bergen Det medisinsk-odontologiske fakultet, Bergen, Norway
  • Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Schell, Christoph, Albert-Ludwigs-Universitat Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Anderson-Fabry disease is an X-linked lysosomal disorder characterized by a multisystemic globotriaosylceramides (Gb3) accumulation due to reduced alpha-galactosidase activity (GLA). Current therapies for Fabry disease are based on reversing intra-cellular accumulation 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.


We employed CRISPR/CAS9 to generate GLA knock out lines of immortalized human podocytes in-vitro. These cells were investigated by (ultra-)structural, transcriptome and proteome as well as functional analyses in the presence and absence ERT. The acquired data sets were integrated through network analysis and connectivity mapping. These data were complimented by the investigation of human biopsies taken sequentially before and after a period of ERT.


Ultrastructural analysis of sequential renal biopsies showed that ERT use reduced Gb3 accumulation in podocytes but did not reverse foot process widening. The a-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.