Abstract text (incl. figure legends and references)
Introduction:
Wild type transthyretin-derived amyloid (ATTRwt) is the major component of non-hereditary transthyretin amyloidosis. Its accumulation in the heart of elderly patients is life threatening. A variety of genetic variants of transthyretin can lead to hereditary transthyretin amyloidosis, which shows different clinical symptoms, like age of onset and pattern of organ involvement. However, in the case of non-hereditary and in some cases of hereditary ATTR amyloidosis fibril deposits are located primarily in heart tissue.
Objectives:
The goal of this study was the analysis of ATTRwt amyloid fibrils structure from the heart of a patient with non-hereditary transthyretin amyloidosis and comparison with previous published structures.
Materials & methods:
Fibrils were extracted from the amyloidotic tissue of an explanted heart of a male ATTRwt patient. Cryo electron microscopy with subsequent structure modelling and mass spectrometry was used to study these fibrils.
Results:
A density map of ex vivo ATTRwt fibrils with a resolution of 2.78 Å was reconstructed. The structure is formed by stacked N- and C-terminal fragments of transthyretin forming an amyloid fibril which was confirmed with mass spectrometry. They form a spearhead like shape in their cross section. The N-terminal fragment has an extensive hydrophobic core. The C-terminal fragment on the other hand contains a big cavity surrounded by polar and charged amino acids and is probably filled with water.
Conclusion:
We compare the structure of ATTRwt fibrils with previously published V30M variants of ATTR fibrils extracted from heart and eye of different patients. All so far published structures show a remarkably similar cross-sectional shape of the N- and C-terminal fragments with only some minor differences. This demonstrates common features for ATTR fibrils despite differences in mutations and patients.