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

Binh An Nguyen, Virender Singh, Shumaila Afrin, Anna Yakubovska, Lanie Wang, Yasmin Ahmed, Rose Pedretti, Maria del Carmen Fernandez-Ramirez, Preeti Singh, Maja Pękała, Luis O. Cabrera Hernandez, Siddharth Kumar, Andrew Lemoff, Roman Gonzalez-Prieto, Michael R. Sawaya, David S. Eisenberg, Merrill Douglas Benson and Lorena Saelices ()
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Binh An Nguyen: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Virender Singh: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Shumaila Afrin: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Anna Yakubovska: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Lanie Wang: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Yasmin Ahmed: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Rose Pedretti: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Maria del Carmen Fernandez-Ramirez: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Preeti Singh: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Maja Pękała: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Luis O. Cabrera Hernandez: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Siddharth Kumar: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)
Andrew Lemoff: University of Texas Southwestern Medical Center
Roman Gonzalez-Prieto: Andalusian Center for Molecular Biology and regenerative Medicine (CABIMER), Universidad de Sevilla-CSIC-Universidad-Pablo de Olavide, Departmento de Biología Celular, Facultad de Biología, Universidad de Sevilla
Michael R. Sawaya: University of California, Los Angeles, Howard Hughes Medical Institute
David S. Eisenberg: University of California, Los Angeles, Howard Hughes Medical Institute
Merrill Douglas Benson: Indiana University School of Medicine
Lorena Saelices: Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (UTSW)

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44820-3

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