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@ARTICLE{Kimura:893173,
author = {Kimura, Kenichi and Ooms, Astrid and Graf-Riesen, Kathrin
and Kuppusamy, Maithreyan and Unger, Andreas and Schuld,
Julia and Daerr, Jan and Lother, Achim and Geisen, Caroline
and Hein, Lutz and Takahashi, Satoru and Li, Guang and
Röll, Wilhelm and Bloch, Wilhelm and van der Ven, Peter F.
M. and Linke, Wolfgang A. and Wu, Sean M. and Huesgen,
Pitter F. and Höhfeld, Jörg and Fürst, Dieter O. and
Fleischmann, Bernd K. and Hesse, Michael},
title = {{O}verexpression of human {BAG}3{P}209{L} in mice causes
restrictive cardiomyopathy},
journal = {Nature Communications},
volume = {12},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {FZJ-2021-02607},
pages = {3575},
year = {2021},
note = {grant ID: DFG Forschergruppe 2743 Mechanical Stress
Protection. DFG Projektnummer 401331881Teilprojekt 3:
Mechanosensoren unter Stress - Entschlüsselung der
Wechselwirkung zwischen Proteinentfaltung, Signalgebung und
Proteolyse},
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.},
cin = {ZEA-3},
ddc = {500},
cid = {I:(DE-Juel1)ZEA-3-20090406},
pnm = {524 - Molecular and Cellular Information Processing
(POF4-524)},
pid = {G:(DE-HGF)POF4-524},
typ = {PUB:(DE-HGF)16},
pubmed = {34117258},
UT = {WOS:000663757400001},
doi = {10.1038/s41467-021-23858-7},
url = {https://juser.fz-juelich.de/record/893173},
}