Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

Kenichi Kimura, Astrid Ooms, Kathrin Graf-Riesen, Maithreyan Kuppusamy, Andreas Unger, Julia Schuld, Jan Daerr, Achim Lother, Caroline Geisen, Lutz Hein, Satoru Takahashi, Guang Li, Wilhelm Röll, Wilhelm Bloch, Peter F. M. Ven, Wolfgang A. Linke, Sean M. Wu, Pitter F. Huesgen, Jörg Höhfeld, Dieter O. Fürst, Bernd K. Fleischmann () and Michael Hesse ()
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Kenichi Kimura: University of Bonn
Astrid Ooms: University of Bonn
Kathrin Graf-Riesen: University of Bonn
Maithreyan Kuppusamy: Forschungszentrum Jülich
Andreas Unger: University of Münster
Julia Schuld: University of Bonn
Jan Daerr: University of Bonn
Achim Lother: University of Freiburg
Caroline Geisen: University of Bonn
Lutz Hein: University of Freiburg
Satoru Takahashi: University of Tsukuba
Guang Li: Stanford University School of Medicine
Wilhelm Röll: University of Bonn
Wilhelm Bloch: German Sport University Cologne, Department of Molecular and Cellular Sport Medicine
Peter F. M. Ven: University of Bonn
Wolfgang A. Linke: University of Münster
Sean M. Wu: Stanford University School of Medicine
Pitter F. Huesgen: Forschungszentrum Jülich
Jörg Höhfeld: University of Bonn
Dieter O. Fürst: University of Bonn
Bernd K. Fleischmann: University of Bonn
Michael Hesse: University of Bonn

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

Date: 2021
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DOI: 10.1038/s41467-021-23858-7

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