Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.48907
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Funding
- Novo Nordisk Foundation [NNF14CC0001]
- Synapsis Foundation - Alzheimer Research Switzerland
- Heidi-Seiler Stiftung
- Swiss National Science Foundation [CRSII3_154461, CRSII5_177195, 20020_178792]
- Agence Nationale de la Recherche [ANR-12-BS08-0013-01]
- Labex [ANR-11-LABX-0048]
- EU Framework Programme for Research and Innovation H2020 [116060 IMPRiND]
- SERI [17.00038]
- Fondation Bettencourt Schueller
- Fondation pour la Recherche Medicale [DEQ 20160334896]
- Fondation Simone et Cino Del Duca [ANR-17-JPCD-0002-02]
- EU [ANR-17-JPCD-0005-01]
- French Infrastructure for Integrated Structural Biology [ANR-10-INSB-05-01]
- University of Lyon Investissements d'Avenir [ANR-11-IDEX-0007]
- Swiss National Science Foundation
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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 angstrom and 3.4 angstrom 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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