Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
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.
Data availability
Raw cryo-EM micrographs are available in EMPIAR, entry numbers EMPIAR-10323. The 3D maps are available in the EMDB, entry numbers EMD-10307 (α-Syn polymorph 2a) and EMD-10305 (α-Syn-polymorph 2b). Atomic coordinates are available at the PDB with entry numbers PDB 6SSX (α-Syn polymorph 2a) and PDB 6SST (α-Syn polymorph 2b).
Article and author information
Author details
Funding
Novo Nordisk (NNF14CC0001)
- Nicholas MI Taylor
SERI (17.00038)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Fondation Bettencourt Schueller
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
fondation pour la Recherche Medicale (Contract DEQ 20160334896)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Fondation Simone et Cino Del Duca of the Institut de France and
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (TransPathND)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
FRISBI (ANR-10-INSB-05-01)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0005-01)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (ANR-17-JPCD-0002-02)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
EC Joint Program on Neurodegenerative Diseases (Protest-70)
- Ana-Andreea Arteni
- Beat H Meier
- Luc Bousset
Synapsis Foundation (n/a)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Heidi-Seiler Stiftung (n/a)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII3_154461)
- Ricardo Guerrero-Ferreira
- Nicholas MI Taylor
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CRSII5_177195)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (20020_178792)
- Ricardo Guerrero-Ferreira
- Henning Stahlberg
Agence Nationale de la Recherche (ANR-12-BS08-0013-01)
- Ronald Melki
- Luc Bousset
LABEX ECOFECT (ANR-11-LABX-0048)
- Anja Böckmann
H2020 (IMPRiND)
- Ana-Andreea Arteni
- Ronald Melki
- Luc Bousset
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Sjors HW Scheres, MRC Laboratory of Molecular Biology, United Kingdom
Version history
- Received: May 30, 2019
- Accepted: November 30, 2019
- Accepted Manuscript published: December 9, 2019 (version 1)
- Version of Record published: January 13, 2020 (version 2)
Copyright
© 2019, Guerrero-Ferreira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 7,886
- Page views
-
- 1,221
- Downloads
-
- 178
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
- Neuroscience
Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot be replenished on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse onward during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus providing synaptic vesicles for synchronous (syt1) and asynchronous (Doc2 and other unidentified sensors) release during ongoing transmission.
-
- Developmental Biology
- Neuroscience
The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.