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- EMDB-75514: Structure of amplified aSyn filament by using seed amplification ... -

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Basic information

Entry
Database: EMDB / ID: EMD-75514
TitleStructure of amplified aSyn filament by using seed amplification assay (SAA) from MSA patient CSF.
Map data
Sample
  • Complex: Alpha-synuclein protein filament
    • Protein or peptide: Alpha-synuclein
KeywordsaSyn filament / Seed amplification assay / amyloid filament / Prion strain / Prion like propagation / 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 ...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 / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of platelet-derived growth factor receptor signaling pathway / negative regulation of exocytosis / regulation of glutamate secretion / dopamine biosynthetic process / response to iron(II) ion / negative regulation of thrombin-activated receptor signaling pathway / SNARE complex assembly / positive regulation of neurotransmitter secretion / negative regulation of dopamine metabolic process / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of locomotion / negative regulation of microtubule polymerization / synaptic vesicle transport / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / mitochondrial ATP synthesis coupled electron transport / positive regulation of receptor recycling / dynein complex binding / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / synaptic vesicle endocytosis / kinesin binding / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / response to type II interferon / regulation of presynapse assembly / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / cellular response to fibroblast growth factor stimulus / phospholipid metabolic process / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / enzyme inhibitor activity / axon terminus / response to interleukin-1 / regulation of microtubule cytoskeleton organization / cellular response to copper ion / positive regulation of release of sequestered calcium ion into cytosol / SNARE binding / adult locomotory behavior / excitatory postsynaptic potential / protein tetramerization / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / PKR-mediated signaling / synapse organization / regulation of long-term neuronal synaptic plasticity / phospholipid binding / receptor internalization / protein destabilization / tau protein binding / terminal bouton / positive regulation of inflammatory response / long-term synaptic potentiation / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cellular response to oxidative stress / neuron apoptotic process / cell cortex / histone binding / response to lipopolysaccharide / microtubule binding / amyloid fibril formation / chemical synaptic transmission / negative regulation of neuron apoptotic process / molecular adaptor activity / mitochondrial outer membrane / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsBanerjee V / Wang F / Baker ML / Serysheva II / Soto C
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
Michael J. Fox Foundation United States
CitationJournal: Nat Commun / Year: 2025
Title: Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates.
Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell ...Authors: Fei Wang / Victor Banerjee / Carla Barria / Santiago Ramirez / Tyler Allison / Damian Gorski / Haley Evans / Quynh Nguyen / Danielle Harrison / Rabab Al-Lahham / Nicole De Gregorio Carbonell / Michelle Pinho / Sanne Kaalund / Jonas Folke / Susana Aznar / Luis Concha-Marambio / Mohd Ishtikhar / Venkata Kps Mallampalli / Sandra Pritzkow / Mohammad Shahnawaz / Matthew L Baker / Irina Serysheva / Claudio Soto /
Abstract: Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence ...Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils retain the biological and structural properties of the αSyn seeds present in MSA brains. We study the biological activities of both brain-derived and SAA-amplified αSyn aggregates using an αSyn "biosensor" cell model and a synucleinopathy transmission mouse model. Our in vitro and in vivo findings reveal that the SAA-amplified αSyn fibrils preserve the biological properties of the brain-derived MSA strain. Detailed analyses of the in vivo studies demonstrate that both brain-derived and SAA-generated αSyn aggregates induce a similar disease, with comparable incubation periods, neuropathological damages and clinical manifestations. High-resolution cryo-EM analysis of SAA-amplified αSyn fibrils demonstrates that their conformation at the protofilament level closely resembles one of the αSyn filaments previously identified in MSA patient brains. Our findings suggest that SAA can amplify disease-specific misfolded αSyn conformation while preserving its main biological properties.
History
DepositionFeb 11, 2026-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75514.png

Downloads & links

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Map

FileDownload / File: emd_75514.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.53 Å/pix.
x 450 pix.
= 238.5 Å		0.53 Å/pix.
x 450 pix.
= 238.5 Å		0.53 Å/pix.
x 450 pix.
= 238.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.53 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0017
Minimum - Maximum-0.005042656 - 0.010266963
Average (Standard dev.)0.000061474544 (±0.00058856374)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 238.49998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_75514_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_75514_half_map_2.map
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Sample components

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Entire : Alpha-synuclein protein filament

EntireName: Alpha-synuclein protein filament
Components
  • Complex: Alpha-synuclein protein filament
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Alpha-synuclein protein filament

SupramoleculeName: Alpha-synuclein protein filament / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.5 kDa/nm

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.607472 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
EGVLYVGSKT KEGVVHGVAT VAEKTKEQVT NVGGAVVTGV TAVAQKTVEG AGSIAAATGF VKKDQLG

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

Concentration1.0 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.41 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.42 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 6698
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

2n0a

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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