Atomic structures of synuclein fibrils

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Guerrero-Ferreira, Stahlberg, Riek, Britschgi and colleagues (Basel and Lausanne, eLife 2018); Peng et al. (Virginia Lee's lab, Penn, Nature 2018); Schweighauser et al. (Goedert and Scheres labs, MRC Laboratory of Molecular Biology, Nature 2020); Yang et al. (Goedert and Scheres, Nature 2022).

What happened

• 2018: The first near-atomic structure of an alpha-synuclein fibril was solved (lab-made, residues 1–121, two protofilaments, 3.4 Å resolution). The same year, Peng et al. showed that alpha-synuclein from multiple system atrophy (MSA) is structurally and biologically different from Lewy body protein: it is more compact and about 1,000 times more potent at seeding new aggregates, and oligodendrocytes, not neurons, convert misfolded protein into the MSA-like strain.
• 2020: Cryo-EM of patient MSA filaments showed two filament types, each made of two different protofilaments, with non-protein molecules at the interface, unlike lab-made fibrils. (The comparison with dementia with Lewy bodies was by 2D class averages only.)
• 2022: Filaments from Parkinson's, Parkinson's dementia and dementia with Lewy bodies brains were shown to share one "Lewy fold" with a single protofilament, unlike MSA.

Why it moved us toward a cure

It shows patient-derived filaments differ from lab-made ones, so antibodies, PET tracers and drugs must target the real disease fold. It also explains why diseases with the same protein behave differently, and gives structure-based targets for Parkinson's.

Outcome

Advanced. Open questions: whether early or non-fibril forms matter more, and whether any drug binds the Lewy fold selectively. Follow-ups include a further MSA filament subtype (Yan et al., FEBS Lett 2025) and matching seeding behaviour and filament structures in FTLD-synuclein (a frontotemporal dementia with synuclein inclusions) and typical MSA (Cullinane et al., Neuropathol Appl Neurobiol 2025). An α-synuclein PET tracer, [18F]ACI-12589, was reported in 2023 to separate MSA from other diseases (Smith et al., Nat Commun 2023); whether it was designed from these structures was not checked.

Corrections. Schweighauser et al. 2020 carries an Author Correction (Nature, 22 Oct 2025): the "DLB Case 1" image in Extended Data Fig. 7 duplicated an MSA cerebellum image in Extended Data Fig. 1 and was replaced; the notice describes no change to the results. No retraction or integrity flag was found for the other three papers (Europe PMC records checked 20 Oct 2026).

Sources

• Guerrero-Ferreira et al., eLife 2018;7:e36402, DOI 10.7554/eLife.36402
• Peng et al., Nature 2018;557:558–563, DOI 10.1038/s41586-018-0104-4
• Schweighauser et al., Nature 2020;585:464–469, DOI 10.1038/s41586-020-2317-6
• Yang et al., Nature 2022;610:791–795, DOI 10.1038/s41586-022-05319-3 · MRC LMB news
• Author Correction to Schweighauser et al., Nature 2025;647:E3, DOI 10.1038/s41586-025-09700-w
• Follow-ups: Yan et al., FEBS Lett 2025;599:33–40, DOI 10.1002/1873-3468.15048 · Cullinane et al., Neuropathol Appl Neurobiol 2025;51:e70013, DOI 10.1111/nan.70013 · Smith et al., Nat Commun 2023;14:6750, DOI 10.1038/s41467-023-42305-3 (abstracts via Europe PMC)
• Not yet verified: number of brains in Yang 2022; structure counts in Schweighauser 2020 beyond the abstract; funders of the four studies; the follow-ups' details beyond their titles and abstracts.