Multiorgan structural analysis by Cryo-EM reveals LEGO-like AA amyloid assemblies

Abstract Mounting evidence shows that structural polymorphism is an intrinsic property of protein assembling into amyloid fibrils. Although it depends on different amyloid systems, the main drivers of polymorphism are different pathologic contexts and mutations, while amyloid structures are generally conserved across individuals and, in systemic amyloidoses, in different organs of the same patient. To shed further light on the role of organ-specific microenvironment in amyloid deposition, here we performed a multiorgan structural characterisation of the amyloid deposits extracted from heart, liver, and kidney of a cat severely affected by AA amyloidosis. Cryo-EM analysis revealed an unprecedented degree of structural heterogeneity. We identified nine distinct amyloid assemblies differing in tertiary structure of the amyloidogenic polypeptide, number of protofilaments, and inter-protofilament interfaces. Protofilament numbers ranged from one to six, while the protein core adopted either a compact or a loose conformation. Four distinct inter-protofilament interfaces were also identified, and their combinations generated additional higher-order architectures. Only one polymorph was detected in all three organs and represented the most abundant species, whereas the remaining polymorphs displayed marked tissue preferences. These findings support a model in which distinct tissue microenvironments promote largely independent aggregation pathways and they challenge the potential role of inter-organ amyloid seeding.