Universität zu Köln

Kimura, Kenichi ORCID: 0000-0002-0363-8865, Ooms, Astrid, Graf-Riesen, Kathrin, Kuppusamy, Maithreyan ORCID: 0000-0001-6866-0417, Unger, Andreas, Schuld, Julia, Daerr, Jan, Lother, Achim, Geisen, Caroline, Hein, Lutz ORCID: 0000-0003-1297-0007, Takahashi, Satoru, Li, Guang, Roell, Wilhelm ORCID: 0000-0002-2213-5024, Bloch, Wilhelm, van der Ven, Peter F. M., Linke, Wolfgang A., Wu, Sean M., Huesgen, Pitter F., Hoehfeld, Jorg, Fuerst, Dieter O., Fleischmann, Bernd K. and Hesse, Michael ORCID: 0000-0002-7518-0224 (2021). Overexpression of human BAG3(P209L) in mice causes restrictive cardiomyopathy. Nat. Commun., 12 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kimura, Kenichi UNSPECIFIED orcid.org/0000-0002-0363-8865 UNSPECIFIED Ooms, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Graf-Riesen, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuppusamy, Maithreyan UNSPECIFIED orcid.org/0000-0001-6866-0417 UNSPECIFIED Unger, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuld, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Daerr, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lother, Achim UNSPECIFIED UNSPECIFIED UNSPECIFIED Geisen, Caroline UNSPECIFIED UNSPECIFIED UNSPECIFIED Hein, Lutz UNSPECIFIED orcid.org/0000-0003-1297-0007 UNSPECIFIED Takahashi, Satoru UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Guang UNSPECIFIED UNSPECIFIED UNSPECIFIED Roell, Wilhelm UNSPECIFIED orcid.org/0000-0002-2213-5024 UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Ven, Peter F. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linke, Wolfgang A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Sean M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Huesgen, Pitter F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehfeld, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuerst, Dieter O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fleischmann, Bernd K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hesse, Michael UNSPECIFIED orcid.org/0000-0002-7518-0224 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-598334
DOI:	10.1038/s41467-021-23858-7
Journal or Publication Title:	Nat. Commun.
Volume:	12
Number:	1
Date:	2021
Publisher:	NATURE RESEARCH
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RNA-SEQ; MYOPATHY; EXPRESSION; AUTOPHAGY; MUTATION; CULTURE; MODELS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59833