Abstract 1610 Leveraging the structures of transthyretin fibrils to understand and detect protein aggregation in ATTR amyloidosis

ATTR amyloidosis is caused by the conversion of transthyretin to amyloid fibrils that deposit in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. In our laboratory we investigate whether the phenotypic variability of ATTR amyloidosis is associated with the structure of transthyretin fibrils and use this information to develop diagnostic tools. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from multiple ATTR amyloidosis patients carrying or not disease-associated mutations. We found that all patients carrying wild-type transthyretin share the same fibril fold, whereas patients carrying hereditary mutations present with distinct structures that can vary from patient to patient and co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril folds in systemic amyloidoses, calling for further studies. Using transthyretin structures, we designed fibril-specific probes that can be used for the detection of ATTR fibrils. Using this tool, we discovered the presence of transthyretin aggregates in ATTR amyloidosis patients. These aggregates appear in individuals carrying disease-associated mutations before showing clinical symptoms of disease. ATTR-modifying treatments result in a reduction of blood aggregates. Our technology may represent a revolutionary tool for early detection of ATTR amyloidosis and treatment monitoring, thereby facilitating clinical assessment and quality of life. This work was supported by the NIH NHLBI DP2-HL163810-01, the People Programme (Marie Curie Actions 298559) of the European Union's 7th Framework Programme, the Amyloidosis Foundation (20160759 and 20170827), the American Heart Association (847236), the Welch Foundation (I-2121-20220331) and UT Southwestern.