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

Nguyen, Binh An; Singh, Virender; Afrin, Shumaila; Yakubovska, Anna; Wang, Lanie; Ahmed, Yasmin; Pedretti, Rose; Fernandez-Ramirez, Maria del Carmen; Singh, Preeti; Pękała, Maja; Cabrera Hernandez, Luis O.; Kumar, Siddharth; Lemoff, Andrew; Gonzalez-Prieto, Roman; Sawaya, Michael R.; Eisenberg, David S.; Benson, Merrill Douglas; Saelices, Lorena

doi:10.1038/s41467-024-44820-3

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

Journal Article · Wed Jan 17 00:00:00 EST 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-44820-3· OSTI ID:2469852

Nguyen, Binh An ^[1]; ^[1]; Afrin, Shumaila ^[1]; Yakubovska, Anna ^[1]; Wang, Lanie ^[1]; Ahmed, Yasmin ^[1]; Pedretti, Rose ^[1]; Fernandez-Ramirez, Maria del Carmen ^[1]; ^[1]; Pękała, Maja ^[1]; ^[1]; Kumar, Siddharth ^[1]; ^[1]; ^[2]; ^[3]; ^[3]; Benson, Merrill Douglas ^[4]; ^[1]

University of Texas Southwestern Medical Center (UTSW), Dallas, TX (United States)
Universidad de Sevilla-CSIC-Universidad-Pablo de Olavide (Spain)
University of California, Los Angeles, CA (United States)
Indiana University School of Medicine, Indianapolis, IN (United States)

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils 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. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: National Institutes for Aging, National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2469852

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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