TY - JOUR
T1 - Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
AU - Nguyen, Binh An
AU - Singh, Virender
AU - Afrin, Shumaila
AU - Yakubovska, Anna
AU - Wang, Lanie
AU - Ahmed, Yasmin
AU - Pedretti, Rose
AU - Fernandez-Ramirez, Maria del Carmen
AU - Singh, Preeti
AU - Pękała, Maja
AU - Cabrera Hernandez, Luis O.
AU - Kumar, Siddharth
AU - Lemoff, Andrew
AU - Gonzalez-Prieto, Roman
AU - Sawaya, Michael R.
AU - Eisenberg, David S.
AU - Benson, Merrill Douglas
AU - Saelices, Lorena
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-024-44820-3
DO - 10.1038/s41467-024-44820-3
M3 - Article
C2 - 38233397
AN - SCOPUS:85182717649
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 581
ER -