Work

Reply to: Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

Year: 2026

Type: preprint

Abstract: In the paper by Nguyen et al, published in Nature Communications in 2024 1 , we describe structural polymorphism in fibrils extracted from patients with ATTR amyloidosis. ATTR amyloidosis is characterized by deposition of transthyretin amyloid fibrils across multiple organs, resulting in marked phenotypic variability. Previous studies on ATTR suggest its phenotypic variability may be linked to differences in fibril structure, as demonstrated in amyloid diseases such as AA amyloidosis, tauopathies, or synucleinopathies 2–4 . Thus far, most ATTR fibrils adopt a strikingly similar fold across patients and affected organs 5–8 . The most notable exception is described in the study by Nguyen et al., where we report the identification of two co-existing polymorphs in cardiac fibrils from three patients with the ATTRv-I84S variant. These cardiac polymorphs differ in conformation of the segment Gly57 to Gly67, termed the gate , which regulates access to a central polar channel within the fibril core. In one polymorph, the gate adopts an open conformation, exposing the channel, whereas in the other it is closed, shielding it 1 . Whether these polymorphs extend beyond cardiac tissue remains unknown. Here, we address this question by extending our analysis to additional organs from a fourth patient with ATTRv-I84S amyloidosis.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.01.755719