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- PDB-9rzf: Structure of in-vivo formed alpha-synuclein fibrils purified from... -

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Basic information

Entry
Database: PDB / ID: 9rzf
TitleStructure of in-vivo formed alpha-synuclein fibrils purified from a M83+/- mouse brain injected with recombinant 1B fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Alpha-synuclein / Prion-like / Fibril / Paired helical filament
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / response to desipramine / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / response to desipramine / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / negative regulation of chaperone-mediated autophagy / regulation of synaptic vesicle recycling / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / dopamine biosynthetic process / dopamine uptake involved in synaptic transmission / negative regulation of dopamine metabolic process / response to iron(II) ion / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of microtubule polymerization / negative regulation of thrombin-activated receptor signaling pathway / synaptic vesicle priming / Lewy body / synaptic vesicle transport / regulation of norepinephrine uptake / synaptic vesicle exocytosis / transporter regulator activity / protein kinase inhibitor activity / positive regulation of inositol phosphate biosynthetic process / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / regulation of dopamine secretion / positive regulation of endocytosis / response to magnesium ion / negative regulation of serotonin uptake / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / supramolecular fiber organization / response to type II interferon / cellular response to epinephrine stimulus / inclusion body / response to interleukin-1 / Hsp70 protein binding / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / enzyme inhibitor activity / glutathione metabolic process / SNARE binding / protein tetramerization / regulation of microtubule cytoskeleton organization / phosphoprotein binding / receptor internalization / protein destabilization / microglial cell activation / tubulin binding / ferrous iron binding / protein sequestering activity / phospholipid binding / synapse organization / PKR-mediated signaling / tau protein binding / enzyme activator activity / positive regulation of inflammatory response / actin cytoskeleton / terminal bouton / synaptic vesicle membrane / negative regulation of neuron apoptotic process / actin binding / response to lipopolysaccharide / growth cone / cellular response to oxidative stress / histone binding / cell cortex / amyloid fibril formation / microtubule binding / oxidoreductase activity / mitochondrial outer membrane / lysosome / transcription cis-regulatory region binding / mitochondrial inner membrane / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / lipid binding / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.8 Å
Authorsvan den Heuvel, L. / Burger, D. / Kashyrina, M. / de La Seigliere, H. / Lewis, A.J. / De Nuccio, F. / Mohammed, I. / Verchere, J. / Feuillie, C. / Berbon, M. ...van den Heuvel, L. / Burger, D. / Kashyrina, M. / de La Seigliere, H. / Lewis, A.J. / De Nuccio, F. / Mohammed, I. / Verchere, J. / Feuillie, C. / Berbon, M. / Arotcarena, M. / Retailleau, A. / Bezard, E. / Canron, M. / Meissner, W.G. / Loquet, A. / Bousset, L. / Poujol, C. / Nilsson, K.P.R. / Laferriere, F. / Baron, T. / Lofrumento, D.D. / De Giorgi, F. / Stahlberg, H. / Ichas, F.
Funding support Switzerland, France, 2items
OrganizationGrant numberCountry
Swiss National Science FoundationIC00I0L-231578 Switzerland
Agence Nationale de la Recherche (ANR)ANR-24-CE93-0003 France
CitationJournal: Nature / Year: 2025
Title: Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology.
Authors: Domenic Burger / Marianna Kashyrina / Lukas van den Heuvel / Hortense de La Seiglière / Amanda J Lewis / Francesco De Nuccio / Inayathulla Mohammed / Jérémy Verchère / Cécile Feuillie / ...Authors: Domenic Burger / Marianna Kashyrina / Lukas van den Heuvel / Hortense de La Seiglière / Amanda J Lewis / Francesco De Nuccio / Inayathulla Mohammed / Jérémy Verchère / Cécile Feuillie / Mélanie Berbon / Marie-Laure Arotcarena / Aude Retailleau / Erwan Bezard / Marie-Hélène Canron / Wassilios G Meissner / Antoine Loquet / Luc Bousset / Christel Poujol / K Peter R Nilsson / Florent Laferrière / Thierry Baron / Dario Domenico Lofrumento / Francesca De Giorgi / Henning Stahlberg / François Ichas /
Abstract: Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 years and leading to death within a decade. It is ...Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 years and leading to death within a decade. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn), the formation of which shows parallels with prion propagation. While fibrils extracted from brains of individuals with MSA have been structurally characterized, their ability to replicate in a protein-only manner has been questioned, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice-suggesting direct relevance to MSA-but lacks scrutiny at the atomic scale. Here we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1B). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1B are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA. Moreover, reinjection of crude mouse brain homogenates containing 1B into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B and 1B that may underlie MSA pathology, offering insights for therapeutic strategies.
History
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein
C: Alpha-synuclein
D: Alpha-synuclein
E: Alpha-synuclein
F: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)36,2276
Polymers36,2276
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 6037.906 Da / Num. of mol.: 6 / Mutation: A53T
Source method: isolated from a genetically manipulated source
Details: The fibril was purified from a mouse, this mouse model expresses a humanised version of the alpha-synuclein protein.
Source: (gene. exp.) Homo sapiens (human) / Strain: Hemizygous A53T alpha-synuclein transgenic line M83 / Gene: SNCA, NACP, PARK1 / Organ: Brain / Production host: Mus musculus (house mouse)
Strain (production host): Hemizygous A53T alpha-synuclein transgenic line M83
References: UniProt: P37840
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Alpha-synuclein fibril purified from the brain of a 1B-injected M83+/- mouse
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 14 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Strain: Hemizygous A53T alpha-synuclein transgenic line M83
Source (recombinant)Organism: Mus musculus (house mouse) / Strain: Hemizygous A53T alpha-synuclein transgenic line M83
Buffer solutionpH: 7.4 / Details: 50 mM Tris-HCl, 150 mM NaCl, pH7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
250 mMTris-HClTris-HCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Sarkosyl-insoluble fraction
Specimen supportDetails: The grids were not glow-discharged / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.04 sec. / Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 42812
Details: Images were collected in movie-mode with a total of 936 frames per movie.
EM imaging opticsEnergyfilter name: TFS Selectris X
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1RELION4.0.0particle selectionUsed for manual picking and helical reconstruction
2cryoSPARC4.7.0particle selectionUsed for selection of micrographs
3EPUimage acquisition
5CTFFIND4.1CTF correction
8Coot0.9.8.96model fitting
9UCSF ChimeraX1.6model fitting
14RELION4.0.03D reconstruction
15PHENIX1.21.2model refinement
Image processingDetails: A total of 40 movies was selected for manual picking
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.55 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 3556
Details: Particles selected by manual picking of fibril start and end points
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1913 / Symmetry type: HELICAL
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Details: A rigid-body fit was done using ChimeraX and a subsequent jiggle fit and all-atom refinement was done in Coot.
Atomic model building

3D fitting-ID: 1 / Accession code: 9EUU / Initial refinement model-ID: 1 / PDB-ID: 9EUU

9euu

/ Source name: PDB / Type: experimental model

IDPdb chain-IDChain-ID
1AA
2BB
RefinementHighest resolution: 3.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044350
ELECTRON MICROSCOPYf_angle_d0.7665890
ELECTRON MICROSCOPYf_dihedral_angle_d5.866630
ELECTRON MICROSCOPYf_chiral_restr0.054790
ELECTRON MICROSCOPYf_plane_restr0.004720

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