A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis

作者：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^*

来源：EMBO Molecular Medicine, 2015, 7(10): 1337-1349.

DOI：10.15252/emmm.201505357

• amyloid
• mechano-enzymatic cleavage
• transthyretin

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.

• 出版日期2015-10