Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy

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Abstract

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.

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Most cited references 39

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alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

M Spillantini, R A Crowther, R. Jakes … (1998)

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

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Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.

K. A. Conway, J Harper, P. Lansbury (1998)

Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.

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G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome.

Suzanne Lesage, Mathieu Anheim, Franck Letournel … (2013)

To date, 3 rare missense mutations in the SNCA (α-synuclein) gene and the more frequent duplications or triplications of the wild-type gene are known to cause a broad array of clinical and pathological symptoms in familial Parkinson disease (PD). Here, we describe a French family with a parkinsonian-pyramidal syndrome harboring a novel heterozygous SNCA mutation. Whole exome sequencing of DNA from 3 patients in a 3-generation pedigree was used to identify a new PD-associated mutation in SNCA. Clinical and pathological features of the patients were analyzed. The cytotoxic effects of the mutant and wild-type proteins were assessed by analytical ultracentrifugation, thioflavin T binding, transmission electron microscopy, cell viability assay, and caspase-3 activation. We identified a novel SNCA G51D (c.152 G>A) mutation that cosegregated with the disease and was absent from controls. G51D was associated with an unusual PD phenotype characterized by early disease onset, moderate response to levodopa, rapid progression leading to loss of autonomy and death within a few years, marked pyramidal signs including bilateral extensor plantar reflexes, occasionally spasticity, and frequently psychiatric symptoms. Pathological lesions predominated in the basal ganglia and the pyramidal tracts and included fine, diffuse cytoplasmic inclusions containing phospho-α-synuclein in superficial layers of the cerebral cortex, including the entorhinal cortex. Functional studies showed that G51D α-synuclein oligomerizes more slowly and its fibrils are more toxic than those of the wild-type protein. We have identified a novel SNCA G51D mutation that causes a form of PD with unusual clinical, neuropathological, and biochemical features. Copyright © 2013 American Neurological Association.

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Author and article information

Contributors

Anja Böckmann:

ORCID: https://orcid.org/0000-0001-8149-7941

Luc Bousset

Henning Stahlberg:

ORCID: https://orcid.org/0000-0002-1185-4592

Sjors HW Scheres: Role: Reviewing Editor

John Kuriyan: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 09 December 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e48907

Affiliations

[1 ]deptCenter for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum University of Basel BaselSwitzerland

[2 ]deptStructural Biology of Molecular Machines Group, Protein Structure & Function Programme, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences University of Copenhagen CopenhagenDenmark

[3 ]Institut de Biologie Intégrative de la Cellule (I2BC), CEA, CNRS, Université Paris Sud, Université Paris-Saclay Gif-sur-YvetteFrance

[4 ]Institut Fancois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS Fontenay-Aux-RosesFrance

[5 ]deptLaboratory of Physical Chemistry ETH Zurich ZurichSwitzerland

[6 ]deptRoche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Medicine Area, Neuroscience Discovery Roche Innovation Center Basel BaselSwitzerland

[7 ]deptRoche Pharma Research and Early Development, Therapeutic Modalities Roche Innovation Center Basel BaselSwitzerland

[8 ]Institut Galien Paris-Sud, CNRS, Université Paris-Sud, Université Paris-Saclay Châtenay-MalabryFrance

[9 ]deptMolecular Microbiology and Structural Biochemistry Labex Ecofect, UMR 5086 CNRS, Université de Lyon LyonFrance

MRC Laboratory of Molecular Biology United Kingdom

University of California, Berkeley United States

MRC Laboratory of Molecular Biology United Kingdom

Author notes

[†]

Robert P Apkarian Integrated Electron Microscopy Core, Emory University School of Medicine, Atlanta, United States.

Author information

Ricardo Guerrero-Ferreira https://orcid.org/0000-0002-3664-8277

Nicholas MI Taylor http://orcid.org/0000-0003-0761-4921

Ana-Andreea Arteni https://orcid.org/0000-0001-6462-905X

Philippe Ringler https://orcid.org/0000-0003-4346-5089

Markus Britschgi https://orcid.org/0000-0001-6151-4257

Matthias E Lauer https://orcid.org/0000-0003-3252-8718

Beat H Meier http://orcid.org/0000-0002-9107-4464

Anja Böckmann https://orcid.org/0000-0001-8149-7941

Henning Stahlberg https://orcid.org/0000-0002-1185-4592

Article

Publisher ID: 48907

DOI: 10.7554/eLife.48907

PMC ID: 6957273

PubMed ID: 31815671

SO-VID: 20f422a5-f400-444d-a328-086d5fd9dc72

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 30 May 2019

Date accepted : 30 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100009708, Novo Nordisk Foundation;

Award ID: NNF14CC0001

Award Recipient : Nicholas MI Taylor

Funded by: FundRef http://dx.doi.org/10.13039/501100008947, Synapsis Foundation – Alzheimer Research Switzerland;

Award Recipient : Ricardo Guerrero-Ferreira Henning Stahlberg

Funded by: Heidi-Seiler Stiftung;

Award Recipient : Ricardo Guerrero-Ferreira Henning Stahlberg

Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Swiss National Science Foundation;

Award ID: CRSII3_154461

Award Recipient : Ricardo Guerrero-Ferreira Nicholas MI Taylor Henning Stahlberg

Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Swiss National Science Foundation;

Award ID: CRSII5_177195

Award Recipient : Ricardo Guerrero-Ferreira Henning Stahlberg

Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Swiss National Science Foundation;

Award ID: 20020_178792

Award Recipient : Beat H Meier

Funded by: FundRef http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;

Award ID: ANR-12-BS08-0013-01

Award Recipient : Ronald Melki Luc Bousset

Funded by: FundRef http://dx.doi.org/10.13039/501100004100, Labex;

Award ID: ANR-11-LABX-0048

Award Recipient : Anja Böckmann

Funded by: FundRef http://dx.doi.org/10.13039/100010661, EU Framework Programme for Research and Innovation H2020;

Award ID: 116060 IMPRiND

Award Recipient : Ana-Andreea Arteni Ronald Melki Luc Bousset

Funded by: FundRef http://dx.doi.org/10.13039/100006541, SERI;

Award ID: 17.00038