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