Key result
Overexpression of human BAG3 P209L in mice causes Z-disc disintegration, protein aggregation, and massive fibrosis, resulting in early-onset restrictive cardiomyopathy.
Why the study?
To phenocopy human BAG3P209L-induced childhood cardiomyopathy in mice and gain insight into its underlying disease mechanisms.
The study establishes a humanized transgenic mouse model that successfully phenocopies the severe childhood restrictive cardiomyopathy caused by the BAG3 P209L mutation, providing a platform for studying disease mechanisms.
Provides a humanized mouse model of BAG3 cardiomyopathy; leaves open translation to human mechanisms or therapies.
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.
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Kimura et al. (2021) studied Restrictive cardiomyopathy. Overexpression of human BAG3 P209L vs. Wild-type or control mice was evaluated on Development of restrictive cardiomyopathy and protein aggregation. Overexpression of human BAG3 P209L in mice causes Z-disc disintegration, protein aggregation, and massive fibrosis, resulting in early-onset restrictive cardiomyopathy.
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