TY  - JOUR
AU  - Kimura, Kenichi
AU  - Ooms, Astrid
AU  - Graf-Riesen, Kathrin
AU  - Kuppusamy, Maithreyan
AU  - Unger, Andreas
AU  - Schuld, Julia
AU  - Daerr, Jan
AU  - Lother, Achim
AU  - Geisen, Caroline
AU  - Hein, Lutz
AU  - Takahashi, Satoru
AU  - Li, Guang
AU  - Röll, Wilhelm
AU  - Bloch, Wilhelm
AU  - van der Ven, Peter F. M.
AU  - Linke, Wolfgang A.
AU  - Wu, Sean M.
AU  - Huesgen, Pitter F.
AU  - Höhfeld, Jörg
AU  - Fürst, Dieter O.
AU  - Fleischmann, Bernd K.
AU  - Hesse, Michael
TI  - Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2021-02607
SP  - 3575
PY  - 2021
N1  - grant ID: DFG Forschergruppe 2743 Mechanical Stress Protection. DFG Projektnummer 401331881Teilprojekt 3: Mechanosensoren unter Stress - Entschlüsselung der Wechselwirkung zwischen Proteinentfaltung, Signalgebung und Proteolyse
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 34117258
UR  - <Go to ISI:>//WOS:000663757400001
DO  - DOI:10.1038/s41467-021-23858-7
UR  - https://juser.fz-juelich.de/record/893173
ER  -