α-Synuclein strains target distinct brain regions and cell types

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Abstract

The clinical and pathological differences between synucleinopathies such as Parkinson’s disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that α-synuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.

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Fig. 1: Generation and characterization of recombinant α-synuclein fibril strains.
Fig. 2: Serial propagation of recombinant and brain-derived α-synuclein strains in TgM83 mice.
Fig. 3: α-Synuclein strains target distinct brain regions in TgM83 mice.
Fig. 4: The NS-fibril-derived and M83+/+-derived α-synuclein strains selectively target astrocytes in TgM83 mice.
Fig. 5: Conformational discrimination of α-synuclein strains in the brains of inoculated TgM83 mice.
Fig. 6: PMCA-generated α-synuclein fibrils produce a phenotype similar to that induced by S fibrils after propagation in TgM83 mice.
Fig. 7: Conformational discrimination of α-synuclein strains in human synucleinopathies.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Source data for Figs. 1 and 5–7 and Extended Data Figs. 4 and 7–10 are presented with the paper.

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Acknowledgements

The authors thank M. Diamond (UT Southwestern) for providing the HEK293 cells expressing YFP-tagged α-synuclein(A53T) and C. Sato and P. St George-Hyslop for providing tissue from the Canadian Brain Tissue Bank. This work was supported by a new investigator award from Parkinson Canada/Pedalling for Parkinson’s (to J.C.W.), grant no. MOP-136899 from the Canadian Institutes of Health Research (to J.C.W.), the Royal Society and an ERC Advanced Grant no. 669237 (to D.K.), Alberta Alzheimer’s Research Program award no. APRI201700005 (to S.C.F. and H.W.), an Ontario Graduate Scholarship (to A.L.), a scholarship from the Croucher Foundation (to R.W.L.S.), a Cambridge Trust Scholarship and a Ministry of Education Technologies Incubation Scholarship, Republic of China (Taiwan) (to J.C.S.), and by a Ramon Jenkins Research Fellowship from Sidney Sussex College Cambridge (to G.M.).

Author information

Designed the experiments: D.K. and J.C.W. Conducted the experiments: A.L., R.W.L.S., H.H.C.L., J.C.S., A.R.-R., S.C.F., E.S., S.M., N.P.V., R.F., M.M.M., C.S.-U. and Z.W. Analyzed and interpreted the data: A.L., G.M., P.E.F., A.T., B.T.H., H.W., M.I., D.K. and J.C.W. Wrote the manuscript: J.C.W. All authors edited and approved the manuscript.

Correspondence to Joel C. Watts.

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Extended data

Extended Data Fig. 1 Non-normalized data for curcumin fluorescence spectral assay.

S fibrils, NS fibrils, or non-polymerized (monomeric) forms of recombinant α-syn(A53T) were subjected to the curcumin dye-binding assay. Spectra were background-corrected but were not normalized. Only the fibrillar forms of α-syn gave appreciable signal, indicating that the assay is specific for aggregates. Each data point represents the mean relative fluorescence obtained from 3 biologically independent fibril preparations ± s.e.m.

Extended Data Fig. 2 α-Syn fibril strains produce distinct inclusions in a cultured cell bioassay.

a) HEK293 cells expressing YFP-tagged α-syn(A53T) were transduced with monomeric α-syn(A53T), S fibrils, or NS fibrils. Each image depicts representative cells following transduction with independent fibril preparations. Scale bar = 10 μm (applies to all images). b) Cells transduced with S fibrils predominantly develop “globular” inclusions whereas cells transduced with NS fibrils predominantly develop “thread-like” inclusions (***P = 2.8 x 10−12, as determined by a two-tailed t-test). Data is mean ± s.e.m. from 4 biologically independent transductions.

Extended Data Fig. 3 Single-molecule fibril seeding assay for measuring the doubling time of α-syn fibril strains.

a) Schematic of fibril assembly and fragmentation model used to determine the doubling time for α-syn fibril strains. For a given concentration of monomeric α-syn(A53T), the doubling time (t2) is determined by the rate constants for fibril elongation (ke) and fragmentation (kf). b) Representative ThT-stained total internal reflection fluorescence microscopy images at the indicated timepoints following seeding of monomeric α-syn(A53T) with S or NS fibrils. Scale bars = 10 μm. c) Single-molecule quantification of aggregate length as a function of time following seeding with S or NS fibrils. Each data point represents the mean ± s.e.m. from 3 independent seeding reactions.

Extended Data Fig. 4 Additional thermolysin digestions of brain homogenates from inoculated TgM83 mice.

a) Immunoblots of detergent-insoluble α-syn species in brain homogenates from the second or third passage of the S or NS fibril-derived strains in TgM83 mice, with or without digestion with thermolysin (TL). Brain homogenates from asymptomatic TgM83 mice from the second passage of PBS were used as a negative control. b) Immunoblots of detergent-insoluble α-syn species in brain homogenates from the second passage of the MSA- or M83+/+-derived strains in TgM83 mice, with or without digestion with TL. In a and b, blots were probed with antibodies to either total α-syn or PSyn. For each inoculum, results from two distinct mice are shown. dpi, days post-inoculation. c) Immunoblots of detergent-insoluble α-syn species in brain homogenates from TgM83 mice inoculated with the indicated α-syn preparations, with or without digestion with TL. Human α-syn was detected with the antibody MJFR1 and mouse α-syn was detected with the antibody D37A6. TL-resistant α-syn species were only present in the animals injected with α-syn aggregates and were only detectable with the antibody specific for human α-syn. Source data

Extended Data Fig. 5 Phosphorylated α-syn (PSyn) deposition in the midbrain and hypothalamus of TgM83 mice injected with various α-syn strains.

a) Representative immunohistochemistry images for PSyn in midbrain and hypothalamus sections from asymptomatic TgM83 mice following inoculation with either PBS or monomeric α-syn, or from clinically ill mice inoculated with either the S fibril- or NS fibril-derived strains (first, second, or third passage). Scale bar = 50 μm (applies to all images). dpi, days post-inoculation. b) Representative immunohistochemistry images for PSyn in midbrain and hypothalamus sections from asymptomatic uninoculated TgM83 mice, or from clinically ill mice inoculated with either the MSA- or M83+/+-derived strains (first or second passage). Scale bar = 50 μm (applies to all images).

Extended Data Fig. 6 Additional immunohistochemical characterization of α-syn inclusions in TgM83 mice inoculated with the S or NS fibril-derived strains.

Representative immunohistochemistry images for either PSyn (midbrain), PK-resistant total α-syn (hypothalamus), or p62 (midbrain) in brain sections from clinically ill TgM83 mice inoculated with either the S fibril- or NS fibril-derived strains (first or second passage). Scale bar = 10 μm (applies to all images). For each experimental group, stainings were performed on a minimum of two mice with similar results.

Extended Data Fig. 7 Comparison of PK-resistant α-syn species generated from recombinant α-syn fibril strains with α-syn species in brain homogenates from fibril-inoculated TgM83 mice.

Immunoblot of detergent-insoluble α-syn species following digestion of recombinant fibrils or brain homogenates from fibril-inoculated TgM83 mice (first passage) with PK. PK-resistant α-syn was detected using the antibody Syn-1. Source data

Extended Data Fig. 8 Additional conformational stability assay (CSA) data for α-syn species in brain homogenates from inoculated TgM83 mice.

a) CSA for PSyn aggregates in clinically ill TgM83 mice inoculated with either the S or NS fibril-derived strains (third passage). Representative PSyn immunoblots and the resultant GdnHCl50 values are shown. The PSyn aggregates in mice inoculated with the NS fibril-derived strain are significantly more stable (**P = 0.0091). Data is mean ± s.e.m (n = 10 mice for the S strain and n = 7 mice for the NS strain). b) CSA for PSyn aggregates in clinically ill TgM83 mice inoculated with either MSA- or M83+/+ brain extract (first passage). Representative PSyn immunoblots and the resultant GdnHCl50 values are shown. Data is mean ± s.e.m (n = 4 for MSA-inoculated mice, n = 6 for M83+/+-inoculated mice). c) CSA for PSyn aggregates in clinically ill TgM83 mice inoculated with either the MSA- or M83+/+-derived strains (second passage). Representative PSyn immunoblots and the resultant GdnHCl50 values are shown. The PSyn aggregates in mice inoculated with the M83+/+-derived strain are significantly more stable (*P = 0.038). Data is mean ± s.e.m (n = 6 for both groups of inoculated mice). All P values were obtained using a two-tailed t-test. Source data

Extended Data Fig. 9 Additional characterization of PMCA-generated α-syn fibrils and PMCA fibril-inoculated TgM83 mice.

a) Kinetics of fibril formation for PMCA fibrils in a ThT fluorescence assay. Reactions incubated at 37 °C in the absence of shaking or sonication (“no PMCA”) were used as a negative control. Each data point represents the mean ± s.e.m of 4 biologically independent replicates. b) Negative stain electron micrograph of PMCA fibrils. The PMCA procedure generated fibrils that were much shorter than either the S or NS fibrils (determined using 3 biologically independent fibril preparations). Scale bar = 200 nm. c) SDS-PAGE followed by silver staining of PK-digested α-syn fibril preparations. PMCA fibrils composed of wild-type (WT) α-syn exhibit a different banding pattern of insoluble PK-resistant α-syn species compared to S fibrils, NS fibrils, and PMCA fibrils composed of A53T-mutant α-syn. d) Immunoblots of detergent-insoluble total α-syn and PSyn species in brain homogenates from two distinct asymptomatic monomer-inoculated mice or clinically ill PMCA fibril-inoculated mice (first passage), with or without digestion with TL. e) Representative immunohistochemistry images for PSyn in midbrain and hypothalamus sections from asymptomatic TgM83 mice following inoculation with monomeric α-syn, or from clinically ill mice inoculated with the PMCA fibril-derived strain (first or second passage). Scale bar = 50 μm (applies to all images). f) GdnHCl50 values for PSyn aggregates in TgM83 mice inoculated with the PMCA fibril-derived strain (first or second passage) are not significantly (ns) different (P = 0.52 for first passage; P = 0.99 for second passage by one-way ANOVA with Tukey’s multiple comparisons test) than for mice inoculated with the S fibril-derived strain (third passage). Data is mean ± s.e.m (n = 5 for first passage PMCA, n = 7 for second passage PMCA, and n = 10 for third passage S strain). g) Immunoblot of PK-digested and detergent-insoluble α-syn species in brain homogenates from clinically ill TgM83 mice inoculated with either the PMCA fibril-derived strain (first or second passage) or the S fibril-derived strain (second passage). Blot was probed with the Syn-1 antibody. Source data

Extended Data Fig. 10 Absence of PSyn pathology in TgM83 mice inoculated with brain extract from a DLB patient or an AD patient with concomitant α-syn deposition.

a) Thermolysin digestion of brain extracts from the three human synucleinopathy samples inoculated into TgM83 mice. α-Syn was detected using the antibody Syn-1. b) Semiquantitative PSyn deposition scoring (data are mean ± s.e.m.) within the indicated brain regions from asymptomatic TgM83 mice at 540 days following inoculation with PBS (first passage, n = 7), DLB brain extract (n = 5), or AD brain extract (n = 4). c) Representative immunohistochemistry images for PSyn in midbrain and hypothalamus sections from asymptomatic TgM83 mice following inoculation with DLB or AD brain extract. Scale bar = 50 μm (applies to all images). Source data

Supplementary information

Supplementary Information

Supplementary Tables 1–4.

Reporting Summary

Supplementary Video 1

Normal hindlimb movement in an asymptomatic TgM83 mouse at 400 d.p.i. with brain extract from a PBS-inoculated TgM83 mouse (PBS second passage).

Supplementary Video 2

Hindlimb shaking phenotype in a symptomatic TgM83 mouse at 323 d.p.i. with NS fibrils (first passage).

Supplementary Video 3

Hindlimb paralysis phenotype in a symptomatic TgM83 mouse at 310 d.p.i. with the S-fibril-derived strain (second passage).

Supplementary Video 4

Hindlimb shaking phenotype in a symptomatic TgM83 mouse at 382 d.p.i. with the NS-fibril-derived strain (second passage).

Supplementary Video 5

Hindlimb paralysis phenotype in a symptomatic TgM83 mouse at 163 d.p.i. with the S-fibril-derived strain (third passage).

Supplementary Video 6

Hindlimb shaking phenotype in a symptomatic TgM83 mouse at 297 d.p.i. with the NS-fibril-derived strain (third passage).

Supplementary Video 7

Hindlimb shaking phenotype in a symptomatic TgM83 mouse at 408 d.p.i. with M83+/+ brain extract (first passage).

Supplementary Video 8

Hindlimb shaking phenotype in a symptomatic TgM83 mouse at 238 d.p.i. with the M83+/+-derived strain (second passage).

Supplementary Video 9

Hindlimb paralysis phenotype in a symptomatic TgM83 mouse at 156 d.p.i. with PMCA fibrils (first passage).

Supplementary Video 10

Hindlimb paralysis phenotype in a symptomatic TgM83 mouse at 200 d.p.i. with the PMCA-fibril-derived strain (second passage).

Source data

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Lau, A., So, R.W.L., Lau, H.H.C. et al. α-Synuclein strains target distinct brain regions and cell types. Nat Neurosci (2019) doi:10.1038/s41593-019-0541-x

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