Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

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 BAG3 P209L -eGFP...

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Published inNature communications Vol. 12; no. 1; pp. 1 - 17
Main Authors Kimura, Kenichi, Ooms, Astrid, Graf-Riesen, Kathrin, Kuppusamy, Maithreyan, Unger, Andreas, Schuld, Julia, Daerr, Jan, Lother, Achim, Geisen, Caroline, Hein, Lutz, Takahashi, Satoru, Li, Guang, Röll, Wilhelm, Bloch, Wilhelm, van der Ven, Peter F. M., Linke, Wolfgang A., Wu, Sean M., Huesgen, Pitter F., Höhfeld, Jörg, Fürst, Dieter O., Fleischmann, Bernd K., Hesse, Michael
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 11.06.2021
Nature Publishing Group UK
Nature Portfolio
Subjects
Age
Amino acids
Animal models
Autophagy
Binding sites
Cardiomyopathy
Children
Control systems
Disintegration
Fibrosis
Mimicry
Mutation
Phagocytosis
Protein interaction
Proteins
Proteomics
Quality control
Rodents
Sequestering
Transgenic mice
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Summary: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 BAG3 P209L -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 P209L -eGFP mice. The mutation renders hBAG3 P209L 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 P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-23858-7