Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis

Abstract

Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The pathological and clinical disease manifestations and the number of pathogenic mutational changes in transthyretin are highly diverse, raising the question whether the different mutations may lead to different fibril morphologies. Using cryo-electron microscopy, however, we show here that the fibril structure is remarkably similar in patients that are affected by different mutations. Our data suggest that the circumstances under which these fibrils are formed and deposited inside the body - and not only the fibril morphology - are crucial for defining the phenotypic variability in many patients.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

“…The density map of the single fibrils exhibited structural consistency with previously published ATTR fibrils (Fig. 2c) 17,23,25-27 . Using the 2D classification of the double fibrils, we built one initial model, low-pass filtered to 20 Å, and used that as the reference model for 3D classification (Fig 2b).…”

“…c . Structural backbone alignment of ATTRV122Δ (pink) fibrils compared to ATTRwt (green) fibrils and a group of previously published ATTRv (blue) fibril structures, including ATTRI84S, ATTRV30M, ATTRV30I, ATTRG47E, and ATTRV122I fibrils 16,17,25 . We have purposefully excluded polymorphic ATTR-I84S fibrils from this alignment because our objective with this analysis is to show the similarity of this particular fibril morphology across multiple genetic backgrounds, with an r.m.s.d.…”

Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM

“…We started this quest after recent cryo-EM studies of brain fibrils from patients of neurodegenerative diseases revealed that each disease is associated with specific fibril conformation(s), suggesting a connection between fibril structure and pathology (Arseni et al, 2022; Fitzpatrick et al, 2017; Scheres et al, 2020; Schweighauser et al, 2020; Yang et al, 2022). Our data, together with the studies from others (Iakovleva et al, 2021; Schmidt et al, 2019; Steinebrei et al, 2023; Steinebrei et al, 2022), revealed that all ATTR fibrils share a common core composed by two TTR fragments with a polar pocket formed by the C-terminal fragment. The two fragments interact by a three-sided interface of interdigitated steric zippers (B.…”

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

“…In contrast to ATTRv-I84S fibrils 22 , the conformation of all ATTRwt fibril structures include a polar channel that resembles a pentagon, starting at Leu 58 and closing at Ile 84. This channel is present in other five ATTR fibril structures from patients with cardiomyopathy or mixed phenotypes [23][24][25] .…”

“…Ten cryo-EM structures of ATTR fibrils have been reported to date 7,21,22 . Cardiac fibrils from five patients with ATTRv-V30M, ATTRv-V20I, ATTRv-G47E, ATTRv-V122I, and ATTRwt genetic backgrounds are structurally homogeneous, sharing the same common core encompassing two fragments [23][24][25] . In all these structures, the C-terminal fragment folds into a channel made of polar residues that runs throughout the fibril.…”