Paper Citing NAMD - Abstract
Marcoux, Julien; Mangione, P. Patrizia; Porcari, Riccardo; Degiacomi, Matteo T.; Verona, Guglielmo; Taylor, Graham W.; Giorgetti, Sofia; Raimondi, Sara; Sanglier-Cianferani, Sarah; Benesch, Justin L. P.; Cecconi, Ciro; Naqvi, Mohsin M.; Gillmore, Julian D.; Hawkins, Philip N.; Stoppini, Monica; Robinson, Carol V.; Pepys, Mark B.; Bellotti, Vittorio
A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
EMBO MOLECULAR MEDICINE, 7:1337-1349, OCT 2015
The mechanisms underlying transthyretin-related amyloidosis invivo remain unclear. The abundance of the 49-127 transthyretin fragment in exvivo 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 invivo. 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.
