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Structures of α-synuclein filaments from human brains with Lewy pathology

Abstract

Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.

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Fig. 1: Cryo-EM cross-sections of α-synuclein filaments (Lewy fold).
Fig. 2: Cryo-EM structure of α-synuclein filaments from Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies (Lewy fold).
Fig. 3: Comparison of the Lewy and MSA α-synuclein filament folds.

Data Availability

Cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession number 15285. Corresponding refined atomic models have been deposited in the Protein Data Bank (PDB) under accession number 8A9L.

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Acknowledgements

We thank the patients’ families for donating brain tissues, T. Darling and J. Grimmett for help with high-performance computing and the EM facility of the Medical Research Council (MRC) Laboratory of Molecular Biology for help with cryo-EM data acquisition. We thank H. Braak, R.A. Crowther, K. Del Tredici, S. Lövestam, W. Poewe, M.G. Spillantini and E. Tolosa for helpful discussions. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s Electron Bio-imaging Centre (under proposal bi23268), funded by the Wellcome Trust, the MRC and the Biotechnology and Biological Sciences Research Council (BBSRC). This work was supported by the MRC (MC_UP_A025_1013 to S.H.W.S. and MC_U105184291 to M.G.). T.L. holds an Alzheimer’s Research UK Senior Fellowship. T.R. is supported by the National Institute for Health Research Queen Square Biomedical Research Unit in Dementia. The Queen Square Brain Bank is supported by the Rita Lila Weston Institute for Neurological Studies. This work was also supported by the Japan Agency for Science and Technology (CREST) (JPMJCR18H3 to M.H.), the Japan Agency for Medical Research and Development (AMED) (JP20dm0207072 to M.H.), the US National Institutes of Health (P30-AG010133, U01-NS110437 and RF1-AG071177, to R.V. and B.G., and R01NS037167, to T.F.) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (to R.V. and B.G.).

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P.W.C., Y. Saito, T.F., T.T.W., K.H., S.M., T.R., B.G., M.H. and T.L. identified patients and performed neuropathology. Y.Y., H.J.G., R.V. and M.H. performed analysis of brain samples. Y.Y., Y. Shi, M.S., X.Z. and A.K. collected cryo-EM data. Y.Y., Y. Shi, M.S., A.G.M. and S.H.W.S. analysed cryo-EM data. Y.Y. performed immunoblot analysis. B.G., M.H. and T.L. performed immunohistochemistry. S.H.W.S. and M.G. supervised the project. All authors contributed to the writing of the manuscript.

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Correspondence to Sjors H. W. Scheres or Michel Goedert.

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Extended data figures and tables

Extended Data Fig. 1 Immunostaining of α-synuclein inclusions.

Sections from brain regions contralateral to those used for cryo-EM structure determination were stained with monoclonal antibody Syn1 (1:1,000). (a), Cingulate cortex from PD; (b), Cingulate cortex from PDD1; (c), Cingulate cortex from PDD2; (d), Frontal cortex from DLB1; (e), Frontal cortex from DLB2; (f), Cingulate cortex from DLB3. Scale bars: a-c, f, 100 μm; d,e, 50 μm.

Extended Data Fig. 2 Negative-stain immunoelectron microscopy and immunoblotting of sarkosyl-insoluble material.

PER4 was used at 1:50 in (a–c). (a), PD (Cingulate cortex); (b), PDD1 (Cingulate cortex); (c), DLB3 (Cingulate cortex); Syn303, Syn1 and PER4 were used at 1:4,000 in (d–f). The brain regions used for cryo-EM were also used for immunoblotting. The arrow points to the position of monomeric α-synuclein.

Extended Data Fig. 3 Cryo-EM maps, cryo-EM images and resolution estimates.

(a), α-Synuclein filaments (blue arrows) from PDD1. Scale bars, 50 nm. (b), Projection features of Lewy filament. Scale bars, 5 nm. (c), Zoomed-in view of the main chain showing density of the oxygen atoms. (d), Fourier shell correlation (FSC) curves for cryo-EM maps are shown in black; for the final refined atomic model against the final cryo-EM map in red; for the atomic model refined in the first half map against that half map in blue; for the refined atomic model in the first half map against the other half map in yellow. (e), Side view of α-synuclein filaments with the Lewy fold.

Extended Data Fig. 4 Twisted and untwisted filaments in 2D class averages and projections.

(a,c,e,g), 2D class averages without twist for case 1 of PDD; (b,d,f,h) projections of untwisted models with the Lewy fold, rotated by 0, 220, 110 and 310 degrees, respectively, along the first Euler angle (rot). Box size, 640 Å. (i–p) Projections of untwisted models of the type 3 filaments from seeded assembly with MSA brain (EMD-12269, PDB 7NCK), rotated by 0, 22.5, 45, 67.5, 90, 112.5, 135 and 157.5 degrees, respectively. (q–x) Projections of untwisted models with the MSA type IIA-B folds (EMD-10651, PDB 6XYP), rotated by 0, 22.5, 45, 67.5, 90, 112.5, 135 and 157.5 degrees, respectively.

Extended Data Fig. 5 Twisted and untwisted segments coexist within filaments.

(a,b,c), Micrographs of filaments with untwisted and twisted segments. Blue indicates segments that contributed to twisted 2D class averages; red indicates segments that contributed to untwisted 2D class averages.

Extended Data Fig. 6 Comparison of the Lewy fold with structures of α-synuclein filaments from human brains or assembled from recombinant proteins.

(a), Ribbon plot of the Lewy fold; the protein chain is coloured as in Fig. 2. Highlighted by red, orange, yellow, green, blue and purple areas are substructures that are individually shared with other filament structures. These local similarities are indicated with the same coloured areas and the overlays of the corresponding substructures are shown in sticks on the following panels (b-f). (b), Common core structure of MSA Type I and Type II filaments (made of PFIA/IIA 14–47 and PFIB/IIB 41–99), with a shared substructure highlighted in yellow. (c), pY39 α-synuclein protofilament (PDB:6L1T) with two different substructures highlighted in orange and green. (d), N-terminally truncated α-synuclein (40–140) dimeric filament (PDB:7LC9), with two different substructures in its protofilaments, highlighted in blue and yellow. Residue numbers with apostrophes indicate those from the other protofilament. (e), Polymorph 2a filament (PDB:6SSX), with two substructures highlighted in purple and orange. (f), Polymorph 1a filament (PDB:6H6B) contains yellow-coloured substructures in its protofilaments and a red-coloured substructure in their dimeric interface.

Extended Data Fig. 7 Zoomed-in cryo-EM densities around Y39 of α-synuclein in various folds.

(a), model and cryo-EM densities of the Lewy fold. Models are shown as sticks in green; densities as grey mesh. (b), model and cryo-EM densities of the MSA type I fold (6XYO, EMD-10650). Models are shown as sticks in yellow. (c), model and cryo-EM densities of α-synuclein filaments with phosphorylated Y39 (6L1T, EMD-0801). Models are shown as sticks in blue.

Extended Data Table 1 Filament types
Extended Data Table 2 Cryo-EM data acquisition and structure determination

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Yang, Y., Shi, Y., Schweighauser, M. et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature 610, 791–795 (2022). https://doi.org/10.1038/s41586-022-05319-3

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