Structures of dye-bound transthyretin amyloid fibrils from abdominal fat biopsies

Transthyretin (TTR) amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in vital organs, leading to cardiomyopathy (ATTR-CM). Early diagnosis of ATTR-CM remains challenging due to lack of sensitive, rapid screening methods. Here, we report cryo-EM structures of TTR amyloid fibrils extracted from minimally invasive abdominal fat-pad biopsies of three living Ala97Ser ATTR-CM patients. The adipose-derived fibril structures closely mirror those from diseased post-mortem cardiac tissues, validating the use of fat-pad biopsies to investigate the atomic structure of TTR fibrils in living patients. Furthermore, we determined cryo-EM structures of TTR fibrils in complex with two amyloid-binding dyes, Congo Red (CR) and Thioflavin S (ThS), which are widely used in the clinical diagnosis of ATTR-CM. Both CR and ThS predominantly bind to a specific surface arginine site on the TTR fibril via electrostatic interactions. These findings provide structural insights into how small-molecule dyes bind TTR fibrils, offering a molecular foundation for the rational design of TTR-specific tracers to enable early and accurate diagnosis of TTR amyloidosis. Authors show that fat-pad biopsies from living ATTR-CM patients yield TTR fibril structures matching cardiac tissue. Cryo-EM reveals Congo Red and ThS bind a surface arginine site, informing tracer design for earlier, more accurate diagnoses.