Abstract
The deposition of amyloidogenic transthyretin (ATTR) in ATTR amyloidosis leads to an unexplained variety of clinical phenotypes, including cardiomyopathy. In brain amyloid conditions, there is an apparent association between the clinical phenotype and the amyloid fibril structure. Here, we question this phenotype-structure association in cardiac amyloidoses by determining the cryo-electron microscopy structures of fibrils extracted from the hearts of seven ATTR amyloidosis patients. We found that, in contrast to brain fibrils, cardiac ATTR fibrils display a structural polymorphism that is not genotype-specific, can co-exist within the same individual, and is independent of the cardiac phenotype. This polymorphism challenges the current paradigm of “one disease equals one fibril fold” proposed in tauopathies and synucleinopathies, and questions whether a similar structural heterogeneity occurs in other amyloidoses.
One-Sentence Summary Unlike brain amyloid fibrils, cardiac ATTR fibrils are polymorphic independent of genotype and even within the same patient.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We have updated the Structure Stats Table We have updated models and density maps in the figures to depict the latest (PDB-published) structure versions. We have included two new authors that contributed to this work.
