Skip to main content

Research Repository

Advanced Search

A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis

Marcoux, J.; Mangione, P.P.; Porcari, R.; Degiacomi, M.T.; Verona, G.; Taylor, G.W.; Giorgetti, S.; Raimondi, S.; Sanglier-Cianférani, S.; Benesch, J.L.; Cecconi, C.; Naqvi, M.M.; Gillmore, J.D.; Hawkins, P.N.; Stoppini, M.; Robinson, C.V.; Pepys, M.B.; Bellotti, V.

A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis Thumbnail


Authors

J. Marcoux

P.P. Mangione

R. Porcari

G. Verona

G.W. Taylor

S. Giorgetti

S. Raimondi

S. Sanglier-Cianférani

J.L. Benesch

C. Cecconi

M.M. Naqvi

J.D. Gillmore

P.N. Hawkins

M. Stoppini

C.V. Robinson

M.B. Pepys

V. Bellotti



Abstract

The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.

Citation

Marcoux, J., Mangione, P., Porcari, R., Degiacomi, M., Verona, G., Taylor, G., …Bellotti, V. (2015). A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis. EMBO Molecular Medicine, 7(10), 1337-1349. https://doi.org/10.15252/emmm.201505357

Journal Article Type Article
Acceptance Date Jul 29, 2015
Online Publication Date Aug 18, 2015
Publication Date Oct 1, 2015
Deposit Date Jul 26, 2017
Publicly Available Date Aug 7, 2017
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Electronic ISSN 1757-4684
Publisher EMBO Press
Peer Reviewed Peer Reviewed
Volume 7
Issue 10
Pages 1337-1349
DOI https://doi.org/10.15252/emmm.201505357

Files

Published Journal Article (2.2 Mb)
PDF

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
© 2015 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms
of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any
medium, provided the original work is properly cited.





You might also like



Downloadable Citations