eprintid: 10140321
rev_number: 23
eprint_status: archive
userid: 608
dir: disk0/10/14/03/21
datestamp: 2021-12-14 16:33:05
lastmod: 2022-01-11 00:03:09
status_changed: 2021-12-14 16:33:05
type: article
metadata_visibility: show
creators_name: Slamova, I
creators_name: Adib, R
creators_name: Ellmerich, S
creators_name: Golos, MR
creators_name: Gilbertson, JA
creators_name: Botcher, N
creators_name: Canetti, D
creators_name: Taylor, GW
creators_name: Rendell, N
creators_name: Tennent, GA
creators_name: Verona, G
creators_name: Porcari, R
creators_name: Mangione, PP
creators_name: Gillmore, JD
creators_name: Pepys, MB
creators_name: Bellotti, V
creators_name: Hawkins, PN
creators_name: Al-Shawi, R
creators_name: Simons, JP
title: Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G90
keywords: Cardiovascular biology, Experimental models of disease, Molecular medicine, Protein folding, Proteolysis
note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
abstract: Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTRS52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α2-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.
date: 2021-12-07
date_type: published
official_url: http://doi.org/10.1038/s41467-021-27416-z
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1909980
doi: 10.1038/s41467-021-27416-z
pii: 10.1038/s41467-021-27416-z
lyricists_name: Al-Shawi, Raya
lyricists_name: Bellotti, Vittorio
lyricists_name: Ellmerich, Stephan
lyricists_name: Gilbertson, Janet
lyricists_name: Gillmore, Julian
lyricists_name: Hawkins, Philip
lyricists_name: Mangione, Palma
lyricists_name: Pepys, Mark
lyricists_name: Simons, Jonathan Paul
lyricists_name: Taylor, Graham
lyricists_name: Tennent, Glenys
lyricists_id: RALSH99
lyricists_id: VBELL78
lyricists_id: SELLM63
lyricists_id: JAGIL44
lyricists_id: JGILL78
lyricists_id: PNHAW77
lyricists_id: PMANG84
lyricists_id: MBPEP52
lyricists_id: JPSIM62
lyricists_id: GTAYL13
lyricists_id: GATEN17
actors_name: Simons, Jonathan Paul
actors_id: JPSIM62
actors_role: owner
full_text_status: public
publication: Nature Communications
volume: 12
number: 1
article_number: 7112
event_location: England
citation:        Slamova, I;    Adib, R;    Ellmerich, S;    Golos, MR;    Gilbertson, JA;    Botcher, N;    Canetti, D;                                                 ... Simons, JP; + view all <#>        Slamova, I;  Adib, R;  Ellmerich, S;  Golos, MR;  Gilbertson, JA;  Botcher, N;  Canetti, D;  Taylor, GW;  Rendell, N;  Tennent, GA;  Verona, G;  Porcari, R;  Mangione, PP;  Gillmore, JD;  Pepys, MB;  Bellotti, V;  Hawkins, PN;  Al-Shawi, R;  Simons, JP;   - view fewer <#>    (2021)    Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis.                   Nature Communications , 12  (1)    , Article 7112.  10.1038/s41467-021-27416-z <https://doi.org/10.1038/s41467-021-27416-z>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10140321/1/s41467-021-27416-z.pdf
document_url: https://discovery.ucl.ac.uk/id/eprint/10140321/7/41467_2021_27416_MOESM1_ESM.pdf