Journal Article

FZJ-2021-02607

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

Kimura, K. ; Ooms, A. ; Graf-Riesen, K. ; Kuppusamy, M.FZJ* ; Unger, A. ; Schuld, J. ; Daerr, J. ; Lother, A. ; Geisen, C. ; Hein, L. ; Takahashi, S. ; Li, G. ; Röll, W. ; Bloch, W. ; van der Ven, P. F. M. ; Linke, W. A. ; Wu, S. M. ; Huesgen, P. F.FZJ* ; Höhfeld, J. ; Fürst, D. O. ; Fleischmann, B. K. (Corresponding author) ; Hesse, M. (Corresponding author)

2021
Nature Publishing Group UK [London]

This record in other databases:      

Please use a persistent id in citations: http://hdl.handle.net/2128/27990  doi:10.1038/s41467-021-23858-7

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 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.

Note: grant ID: DFG Forschergruppe 2743 Mechanical Stress Protection. DFG Projektnummer 401331881Teilprojekt 3: Mechanosensoren unter Stress - Entschlüsselung der Wechselwirkung zwischen Proteinentfaltung, Signalgebung und Proteolyse

---

Contributing Institute(s):

1. Analytik (ZEA-3)

Research Program(s):

1. 524 - Molecular and Cellular Information Processing (POF4-524) (POF4-524)

Appears in the scientific report 2021

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---