Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

Ivana Slamova, Rozita Adib, Stephan Ellmerich, Michal R. Golos, Janet A. Gilbertson, Nicola Botcher, Diana Canetti, Graham W. Taylor, Nigel Rendell, Glenys A. Tennent, Guglielmo Verona, Riccardo Porcari, P. Patrizia Mangione, Julian D. Gillmore, Mark B. Pepys, Vittorio Bellotti, Philip N. Hawkins, Raya Al-Shawi and J. Paul Simons ()
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Ivana Slamova: University College London
Rozita Adib: University College London
Stephan Ellmerich: University College London
Michal R. Golos: University College London
Janet A. Gilbertson: University College London
Nicola Botcher: University College London
Diana Canetti: University College London
Graham W. Taylor: University College London
Nigel Rendell: University College London
Glenys A. Tennent: University College London
Guglielmo Verona: University College London
Riccardo Porcari: University College London
P. Patrizia Mangione: University College London
Julian D. Gillmore: University College London
Mark B. Pepys: University College London
Vittorio Bellotti: University College London
Philip N. Hawkins: University College London
Raya Al-Shawi: University College London
J. Paul Simons: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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
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DOI: 10.1038/s41467-021-27416-z

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