Abstract: PO1339
Synuclein Alpha Accumulation Drives Lysosomal Dysfunction in Fabry Podocytopathy
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Braun, Fabian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Abed, Ahmed, Universitatsklinikum Freiburg, Freiburg, Baden-Württemberg, Germany
- Woidy, Mathias, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Eikrem, Oystein, Universitetet i Bergen Det medisinsk-odontologiske fakultet, Bergen, Norway
- Wanner, Nicola, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- von Cossel, Katharina Maria, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Gersting, Soeren W., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Muntau, Ania C., 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 Medical School Twin Cities, Minneapolis, Minnesota, United States
- Grahammer, Florian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Eierhoff, Thorsten, Universitatsklinikum Munster, Munster, Nordrhein-Westfalen, Germany
- Marti, Hans-Peter, Universitetet i Bergen Det medisinsk-odontologiske fakultet, Bergen, Norway
- Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Schell, Christoph, Universitatsklinikum Freiburg, Freiburg, Baden-Württemberg, Germany
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background
Anderson-Fabry disease is an X-linked lysosomal disorder characterized by a multisystemic globotriaosylceramides (Gb3) accumulation due to reduced alpha-galactosidase activity (GLA). Podocyte injury is a major renal manifestation of Fabry disease. Recently, our data indicated Gb3 depletion to be insufficient in repairing podocyte damage seen in an in vitro model for Fabry disease. This project, therefore, focused on potential Gb3 independent mechanisms in Fabry podocytopathy.
Methods
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 of enzyme replacement therapy (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.
Results
We detected that enzyme replacement therapy (ERT) and Gb3 reduction failed to ameliorate signs of podocyte injury in patient biopsies. GLA knockout podocytes depicted high Gb3 levels that were fully reversed upon enzyme replacement. Still lysosomal dysfunction was significantly but not completely reversible with enzyme therapy. Proteomics suggested alpha-synuclein (SNCA) accumulation as a potential driver of lysosomal dysfunction. Transcriptomics-based connectivity mapping further revealed a potential anti-SNCA therapeutic effect of beta-adrenoceptor agonists. Indeed, genetic and pharmacological inhibition of this protein significantly improved lysosomal structure and function in Fabry podocytes beyond the effects of ERT.
Conclusion
This study provides strong evidence of a central role of SNCA in lysosomal dysfunction in Fabry disease independent of Gb3 accumulation. The results offer new options for pharmacological strategies to target Fabry podocytopathy.