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Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy.
- Source :
- Nature Communications; 6/11/2021, Vol. 12 Issue 1, p1-17, 17p
- Publication Year :
- 2021
-
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<superscript>P209L</superscript>-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<superscript>P209L</superscript>-eGFP mice. The mutation renders hBAG3<superscript>P209L</superscript> 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<superscript>P209L</superscript> and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption. An amino acid exchange (P209L) in the human co-chaperone BAG3 gives rise to severe childhood restrictive cardiomyopathy. Here the authors describe humanized transgenic mouse models which phenocopy the disease and provide insight into the pathogenic mechanisms. [ABSTRACT FROM AUTHOR]
- Subjects :
- LABORATORY mice
TRANSGENIC mice
CARDIOMYOPATHIES
MICE
QUALITY control
BINDING sites
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 12
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 150854091
- Full Text :
- https://doi.org/10.1038/s41467-021-23858-7