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- EMDB-54402: Structure of in-vivo formed alpha-synuclein fibrils purified from... -

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Entry
Database: EMDB / ID: EMD-54402
TitleStructure of in-vivo formed alpha-synuclein fibrils purified from a M83+/- mouse brain injected with recombinant 1B fibrils
Map dataPostprocessed EM map
Sample
  • Complex: Alpha-synuclein fibril purified from the brain of a 1B-injected M83+/- mouse
    • Protein or peptide: Alpha-synuclein
KeywordsAlpha-synuclein / Prion-like / Fibril / Paired helical filament / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / neutral lipid metabolic process / regulation of acyl-CoA biosynthetic process / negative regulation of dopamine uptake involved in synaptic transmission / negative regulation of norepinephrine uptake / response to desipramine / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / mitochondrial membrane organization / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / positive regulation of neurotransmitter secretion / regulation of macrophage activation / negative regulation of dopamine metabolic process / negative regulation of platelet-derived growth factor receptor signaling pathway / SNARE complex assembly / negative regulation of thrombin-activated receptor signaling pathway / Lewy body / regulation of locomotion / negative regulation of microtubule polymerization / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / regulation of norepinephrine uptake / transporter regulator activity / protein kinase inhibitor activity / synaptic vesicle transport / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / positive regulation of receptor recycling / positive regulation of exocytosis / cuprous ion binding / mitochondrial ATP synthesis coupled electron transport / nuclear outer membrane / dynein complex binding / response to magnesium ion / synaptic vesicle exocytosis / positive regulation of endocytosis / negative regulation of serotonin uptake / response to type II interferon / kinesin binding / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / supramolecular fiber organization / phospholipid metabolic process / behavioral response to cocaine / cellular response to fibroblast growth factor stimulus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / response to interleukin-1 / axon terminus / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / regulation of microtubule cytoskeleton organization / SNARE binding / adult locomotory behavior / glutathione metabolic process / protein tetramerization / excitatory postsynaptic potential / protein sequestering activity / phosphoprotein binding / tubulin binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / regulation of long-term neuronal synaptic plasticity / synapse organization / receptor internalization / phospholipid binding / protein destabilization / tau protein binding / enzyme activator activity / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / growth cone / actin binding / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.8 Å
Authorsvan den Heuvel L / Burger D / Kashyrina M / de La Seigliere H / Lewis AJ / De Nuccio F / Mohammed I / Verchere J / Feuillie C / Berbon M ...van den Heuvel L / Burger D / Kashyrina M / de La Seigliere H / Lewis AJ / De Nuccio F / Mohammed I / Verchere J / Feuillie C / Berbon M / Arotcarena M / Retailleau A / Bezard E / Canron M / Meissner WG / Loquet A / Bousset L / Poujol C / Nilsson KPR / Laferriere F / Baron T / Lofrumento DD / De Giorgi F / Stahlberg H / Ichas F
Funding support Switzerland, France, 2 items
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
DepositionJul 15, 2025-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54402.png

Downloads & links

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Map

FileDownload / File: emd_54402.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed EM map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.46 Å/pix.
x 400 pix.
= 585.6 Å		1.46 Å/pix.
x 400 pix.
= 585.6 Å		1.46 Å/pix.
x 400 pix.
= 585.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.464 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.019
Minimum - Maximum-0.075218976 - 0.11792008
Average (Standard dev.)0.000037732378 (±0.0012426373)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 585.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54402_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Helically symmetrized EM map

Fileemd_54402_additional_1.map
AnnotationHelically symmetrized EM map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 of refinement (unfiltered)

Fileemd_54402_half_map_1.map
AnnotationHalf map 2 of refinement (unfiltered)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1 of refinement (unfiltered)

Fileemd_54402_half_map_2.map
AnnotationHalf map 1 of refinement (unfiltered)
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Alpha-synuclein fibril purified from the brain of a 1B-injected M...

EntireName: Alpha-synuclein fibril purified from the brain of a 1B-injected M83+/- mouse
Components
  • Complex: Alpha-synuclein fibril purified from the brain of a 1B-injected M83+/- mouse
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Alpha-synuclein fibril purified from the brain of a 1B-injected M...

SupramoleculeName: Alpha-synuclein fibril purified from the brain of a 1B-injected M83+/- mouse
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Strain: Hemizygous A53T alpha-synuclein transgenic line M83
Molecular weightTheoretical: 14 kDa/nm

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1
Details: The fibril was purified from a mouse, this mouse model expresses a humanised version of the alpha-synuclein protein.
Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Strain: Hemizygous A53T alpha-synuclein transgenic line M83 / Organ: Brain
Molecular weightTheoretical: 6.037906 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
VLYVGSKTKE GVVHGVTTVA EKTKEQVTNV GGAVVTGVTA VAQKTVEGAG SIAAATGFVK K

UniProtKB: Alpha-synuclein

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
50.0 mMTris-HClTris-HCl

Details: 50 mM Tris-HCl, 150 mM NaCl, pH7.4
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Support film - #0 - Film type ID: 1 / Support film - #0 - Material: CARBON / Support film - #0 - topology: HOLEY ARRAY / Support film - #0 - Film thickness: 12 / Support film - #1 - Film type ID: 2 / Support film - #1 - Material: CARBON / Support film - #1 - topology: CONTINUOUS / Support film - #1 - Film thickness: 5 / Details: The grids were not glow-discharged
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 293 K / Instrument: LEICA EM GP
DetailsSarkosyl-insoluble fraction

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 2 / Number real images: 42812 / Average exposure time: 3.04 sec. / Average electron dose: 50.0 e/Å2
Details: Images were collected in movie-mode with a total of 936 frames per movie.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsA total of 40 movies was selected for manual picking
Final reconstructionApplied symmetry - Helical parameters - Δz: 2.4 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.55 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0.0) / Number images used: 1913
CTF correctionSoftware - Name: CTFFIND (ver. 4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Segment selectionNumber selected: 3556
Software:
Namedetails
RELION (ver. 4.0.0)Used for manual picking and helical reconstruction
cryoSPARC (ver. 4.7.0)Used for selection of micrographs

Details: Particles selected by manual picking of fibril start and end points
Startup modelType of model: INSILICO MODEL
In silico model: Initial model was generated with relion_helix_inimodel2d
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

9euu

chain_id: A, source_name: PDB, initial_model_type: experimental model

9euu

chain_id: B, source_name: PDB, initial_model_type: experimental model
DetailsA rigid-body fit was done using ChimeraX and a subsequent jiggle fit and all-atom refinement was done in Coot.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9rzf:
Structure of in-vivo formed alpha-synuclein fibrils purified from a M83+/- mouse brain injected with recombinant 1B fibrils

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