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Overexpression of human BAG3 in mice causes restrictive cardiomyopathy.

Nature communications

Authors: 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 van der Ven, Wolfgang A Linke, Sean M Wu, Pitter F Huesgen, Jörg Höhfeld, Dieter O Fürst, Bernd K Fleischmann, Michael Hesse

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 BAG3-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 hBAG3-eGFP mice. The mutation renders hBAG3 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 hBAG3 and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

PMID: 34117258

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