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Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

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

In: J CLIN INVEST, Vol. 133, No. 11, e157782, 01.06.2023.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Braun, F, Abed, A, Sellung, D, Rogg, M, Woidy, M, Eikrem, O, Wanner, N, Gambardella, J, Laufer, SD, Haas, F, Wong, MN, Dumoulin, B, Rischke, P, Mühlig, AK, Sachs, W, von Cossel, K, Schulz, K, Muschol, N, Gersting, SW, Muntau, AC, Kretz, O, Hahn, O, Rinschen, MM, Mauer, M, Bork, T, Grahammer, F, Liang, W, Eierhoff, T, Römer, W, Hansen, A, Meyer-Schwesinger, C, Iaccarino, G, Tøndel, C, Marti, H-P, Najafian, B, Puelles, VG, Schell, C & Huber, TB 2023, 'Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy', J CLIN INVEST, vol. 133, no. 11, e157782. https://doi.org/10.1172/JCI157782

APA

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., Mühlig, A. K., Sachs, W., von Cossel, K., Schulz, K., Muschol, N., Gersting, S. W., ... Huber, T. B. (2023). Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy. J CLIN INVEST, 133(11), [e157782]. https://doi.org/10.1172/JCI157782

Vancouver

Braun F, Abed A, Sellung D, Rogg M, Woidy M, Eikrem O et al. Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy. J CLIN INVEST. 2023 Jun 1;133(11). e157782. https://doi.org/10.1172/JCI157782

Bibtex

@article{8db466c0925543ddafd240ccb196f0c2,
title = "Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy",
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.",
keywords = "Fabry Disease/genetics, Humans, Kidney/metabolism, Podocytes/pathology, Trihexosylceramides/metabolism, alpha-Galactosidase/genetics, alpha-Synuclein/genetics",
author = "Fabian Braun and Ahmed Abed and Dominik Sellung and Manuel Rogg and Mathias Woidy and Oysten Eikrem and Nicola Wanner and Jessica Gambardella and Laufer, {Sandra D} and Fabian Haas and Wong, {Milagros N} and Bernhard Dumoulin and Paula Rischke and M{\"u}hlig, {Anne K} and Wiebke Sachs and {von Cossel}, Katharina and Kristina Schulz and Nicole Muschol and Gersting, {S{\"o}ren W} and Muntau, {Ania C} and Oliver Kretz and Oliver Hahn and Rinschen, {Markus M} and Michael Mauer and Tillmann Bork and Florian Grahammer and Wei Liang and Thorsten Eierhoff and Winfried R{\"o}mer and Arne Hansen and Catherine Meyer-Schwesinger and Guido Iaccarino and Camilla T{\o}ndel and Hans-Peter Marti and Behzad Najafian and Puelles, {Victor G} and Christoph Schell and Huber, {Tobias B}",
year = "2023",
month = jun,
day = "1",
doi = "10.1172/JCI157782",
language = "English",
volume = "133",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

RIS

TY - JOUR

T1 - Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

AU - Braun, Fabian

AU - Abed, Ahmed

AU - Sellung, Dominik

AU - Rogg, Manuel

AU - Woidy, Mathias

AU - Eikrem, Oysten

AU - Wanner, Nicola

AU - Gambardella, Jessica

AU - Laufer, Sandra D

AU - Haas, Fabian

AU - Wong, Milagros N

AU - Dumoulin, Bernhard

AU - Rischke, Paula

AU - Mühlig, Anne K

AU - Sachs, Wiebke

AU - von Cossel, Katharina

AU - Schulz, Kristina

AU - Muschol, Nicole

AU - Gersting, Sören W

AU - Muntau, Ania C

AU - Kretz, Oliver

AU - Hahn, Oliver

AU - Rinschen, Markus M

AU - Mauer, Michael

AU - Bork, Tillmann

AU - Grahammer, Florian

AU - Liang, Wei

AU - Eierhoff, Thorsten

AU - Römer, Winfried

AU - Hansen, Arne

AU - Meyer-Schwesinger, Catherine

AU - Iaccarino, Guido

AU - Tøndel, Camilla

AU - Marti, Hans-Peter

AU - Najafian, Behzad

AU - Puelles, Victor G

AU - Schell, Christoph

AU - Huber, Tobias B

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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.

AB - 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.

KW - Fabry Disease/genetics

KW - Humans

KW - Kidney/metabolism

KW - Podocytes/pathology

KW - Trihexosylceramides/metabolism

KW - alpha-Galactosidase/genetics

KW - alpha-Synuclein/genetics

U2 - 10.1172/JCI157782

DO - 10.1172/JCI157782

M3 - SCORING: Journal article

C2 - 37014703

VL - 133

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 11

M1 - e157782

ER -