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Consequences of variability in α-synuclein fibril structure on strain biology

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Abstract

Synucleinopathies are a group of clinically and neuropathologically distinct protein misfolding diseases caused by unique α-synuclein conformations, or strains. While multiple atomic resolution cryo-electron microscopy structures of α-synuclein fibrils are now deposited in Protein Data Bank, significant gaps in the biological consequences arising from each conformation have yet to be unraveled. Mutations in the α-synuclein gene (SNCA), cofactors, and the solvation environment contribute to the formation and maintenance of each disease-causing strain. This review highlights the impact of each of these factors on α-synuclein misfolding and discusses the implications of the resulting structural variability on therapeutic development.

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Acknowledgements

The Woerman Lab is supported by a Venture Grant (668-2020-06) from the CurePSP Foundation and the University of Massachusetts Amherst (A.L.W.). We thank Dr. Steven H. Olson for his thoughtful feedback on and intellectual discussions about the manuscript.

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  1. Samantha L. Liu

    Present address: Molecular and Cellular Biology Program, Dartmouth College, Hanover, NH, USA

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  1. Department of Biology, Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA, USA

    Sara A. M. Holec, Samantha L. Liu & Amanda L. Woerman

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Correspondence to Amanda L. Woerman.

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Holec, S.A.M., Liu, S.L. & Woerman, A.L. Consequences of variability in α-synuclein fibril structure on strain biology. Acta Neuropathol 143, 311–330 (2022). https://doi.org/10.1007/s00401-022-02403-w

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