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.
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Acknowledgements
The authors thank A. Bertolotti, T. Crowther, J. Hardy, S. Lövestam, J. Löwe, J. Macdonald, C. Mathis, A. Murzin, M. G. Spillantini, A. Stern, B. de Strooper, S. Tetter and Y. Yang for helpful comments. We are grateful to past and present members of our groups and facilities at the Medical Research Council Laboratory of Molecular Biology for their contributions. We especially thank B. Ghetti and M. Hasegawa for their long-term collaboration, and family members of the deceased who donated brains. This work was supported by the Medical Research Council, as part of United Kingdom Research and Innovation (MC_UP_A025-1013 to S.H.W.S., MC_UP_1201/25, to B.R.-F. and MC_U105184291 to M.G.).
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Scheres, S.H.W., Ryskeldi-Falcon, B. & Goedert, M. Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids. Nature 621, 701–710 (2023). https://doi.org/10.1038/s41586-023-06437-2
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DOI: https://doi.org/10.1038/s41586-023-06437-2
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Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy
Acta Neuropathologica Communications (2023)
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