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

doi:10.1172/JCI157782

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. MuntauOliver 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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

24 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	e157782
Tidsskrift	The Journal of clinical investigation
Vol/bind	133
Nummer	11
ISSN	0021-9738
DOI	https://doi.org/10.1172/JCI157782
Status	Udgivet - jun. 2023

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10.1172/JCI157782Licens: CC BY

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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., 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. The Journal of clinical investigation, 133(11), Artikel e157782. https://doi.org/10.1172/JCI157782

@article{d8453f1a8fa44a698e55fb550b85765f,

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 = "Chronic kidney disease, Drug therapy, Genetic diseases, Genetics, Nephrology",

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 Anne M{\"u}hlig 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 Marti, {Hans Peter} and Behzad Najafian and Puelles, {Victor G.} and Christoph Schell and Huber, {Tobias B.}",

year = "2023",

month = jun,

doi = "10.1172/JCI157782",

language = "English",

volume = "133",

journal = "The Journal of clinical investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "11",

}

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, A, 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, HP, Najafian, B, Puelles, VG, Schell, C & Huber, TB 2023, 'Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy', The Journal of clinical investigation, bind 133, nr. 11, e157782. https://doi.org/10.1172/JCI157782

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

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

Y1 - 2023/6

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 - Chronic kidney disease

KW - Drug therapy

KW - Genetic diseases

KW - Genetics

KW - Nephrology

UR - http://www.scopus.com/inward/record.url?scp=85160375790&partnerID=8YFLogxK

U2 - 10.1172/JCI157782

DO - 10.1172/JCI157782

M3 - Journal article

C2 - 37014703

AN - SCOPUS:85160375790

SN - 0021-9738

VL - 133

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

IS - 11

M1 - e157782

ER -

Accumulation of α-synuclein mediates podocyte injury in Fabry nephropathy

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