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Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

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  • Sjors H. W. Scheres

    (Medical Research Council Laboratory of Molecular Biology)

  • Benjamin Ryskeldi-Falcon

    (Medical Research Council Laboratory of Molecular Biology)

  • Michel Goedert

    (Medical Research Council Laboratory of Molecular Biology)

Abstract

Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct link between filament formation and the causes of disease. Developments in cryo-electron microscopy (cryo-EM) have made it possible to determine the atomic structures of amyloids from postmortem human brains. Here we review the structures of brain-derived amyloid filaments that have been determined so far and discuss their impact on research into neurodegeneration. Whereas a given protein can adopt many different filament structures, specific amyloid folds define distinct diseases. Amyloid structures thus provide a description of neuropathology at the atomic level and a basis for studying disease. Future research should focus on model systems that replicate the structures observed in disease to better understand the molecular mechanisms of disease and develop improved diagnostics and therapies.

Suggested Citation

  • Sjors H. W. Scheres & Benjamin Ryskeldi-Falcon & Michel Goedert, 2023. "Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids," Nature, Nature, vol. 621(7980), pages 701-710, September.
    • Handle: RePEc:nat:nature:v:621:y:2023:i:7980:d:10.1038_s41586-023-06437-2
    DOI: 10.1038/s41586-023-06437-2
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    Cited by:

    1. 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 Herna, 2024. "Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Chalmers C. Chau & Christopher M. Maffeo & Aleksei Aksimentiev & Sheena E. Radford & Eric W. Hewitt & Paolo Actis, 2024. "Single molecule delivery into living cells," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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