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- EMDB-52833: Cryo-EM structure of alpha-synuclein fibrils formed in artificial... -

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Basic information

Entry
Database: EMDB / ID: EMD-52833
TitleCryo-EM structure of alpha-synuclein fibrils formed in artificial cerebrospinal fluid (aCSF)
Map dataMasked map after relion post-processing
Sample
  • Complex: Amyloid fibrils of alpha-synuclein formed in artificial cerebrospinal fluid
    • Protein or peptide: Alpha-synuclein
KeywordsParkinson / CSF / alpha-synuclein / neurodegeneration / 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 / mitochondrial membrane organization / regulation of reactive oxygen species biosynthetic process / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / negative regulation of platelet-derived growth factor receptor signaling pathway / regulation of glutamate secretion / Lewy body / 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 / regulation of norepinephrine uptake / synaptic vesicle priming / transporter regulator activity / synaptic vesicle transport / protein kinase inhibitor activity / dopamine uptake involved in synaptic transmission / 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 / negative regulation of serotonin uptake / response to type II interferon / synaptic vesicle endocytosis / kinesin binding / regulation of presynapse assembly / cysteine-type endopeptidase inhibitor activity / 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 / glutathione metabolic process / excitatory postsynaptic potential / protein tetramerization / protein sequestering activity / tubulin binding / phosphoprotein binding / microglial cell activation / ferrous iron binding / fatty acid metabolic process / synapse organization / PKR-mediated signaling / regulation of long-term neuronal synaptic plasticity / 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 / neuron apoptotic process / cellular response to oxidative stress / 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: 2.9 Å
AuthorsSnieckute R / Sulskis D / Jocyte A / Venclovaite U / Tamulyte R / Ziaunys M / Smirnovas V / Sakalauskas A
Funding supportLithuania, European Union, 3 items
OrganizationGrant numberCountry
Research Council of LithuaniaS-PD-22-91Lithuania
European Regional Development Fund01.1.1-CPVA-V-701-07-0001European Union
Other government24381
CitationJournal: Adv Sci (Weinh) / Year: 2026
Title: Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid.
Authors: Rūta Sniečkutė / Darius Šulskis / Arūnė Jocytė / Urtė Venclovaitė / Rimgailė Tamulytė / Mantas Žiaunys / Vytautas Smirnovas / Andrius Sakalauskas
Abstract: α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such ...α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such as Parkinson's disease (PD) or Multiple System Atrophy (MSA). Misfolded aSyn, which primarily originates in the cell cytosol, transmits between neurons, promoting a prion-like propagation. However, extracellular environments such as interstitial and cerebrospinal fluids (ISF & CSF) play a major role in its clearance and pathological transformation. The molecular components of CSF, including proteins, glycosaminoglycans, and metal ions, may influence the aggregate morphology, structure, and cytotoxicity to cells. To better understand how extracellular composition affects aggregates and their formation, artificial cerebrospinal fluid (aCSF) is employed to mimic potential aggregation processes occurring in CSF. Distinct aSyn fibrils are observed that exhibited low stability outside aCSF, and the removal of key CSF components led to its structural alterations. Cryo-electron microscopy revealed that these fibrils possess an electron density pocket coordinated with polar basic AAs (K43, K45, H50) that is also observed in aggregates obtained from PD and MSA patients. The findings illustrate the importance of physiologically relevant conditions in studying aSyn aggregation and may explain why disease-related fibril structure replication in vitro has not yet been successful.
History
DepositionFeb 14, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateFeb 18, 2026-
Current statusFeb 18, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52833.png

Downloads & links

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Map

FileDownload / File: emd_52833.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMasked map after relion post-processing
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 384 pix.
= 289.536 Å		0.75 Å/pix.
x 384 pix.
= 289.536 Å		0.75 Å/pix.
x 384 pix.
= 289.536 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.754 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00212
Minimum - Maximum-0.01614527 - 0.03296437
Average (Standard dev.)0.000064903026 (±0.001034443)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 289.536 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Unfiltered half-map 2

Fileemd_52833_half_map_1.map
AnnotationUnfiltered half-map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Unfiltered half-map 1

Fileemd_52833_half_map_2.map
AnnotationUnfiltered half-map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid fibrils of alpha-synuclein formed in artificial cerebrosp...

EntireName: Amyloid fibrils of alpha-synuclein formed in artificial cerebrospinal fluid
Components
  • Complex: Amyloid fibrils of alpha-synuclein formed in artificial cerebrospinal fluid
    • Protein or peptide: Alpha-synuclein

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Supramolecule #1: Amyloid fibrils of alpha-synuclein formed in artificial cerebrosp...

SupramoleculeName: Amyloid fibrils of alpha-synuclein formed in artificial cerebrospinal fluid
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 204.4 KDa

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 14 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.476108 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

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

Concentration0.723 mg/mL
BufferpH: 7.33
Component:
ConcentrationFormulaName
127.0 mMNaClSodium chloride
1.8 mMKClPotassium chloride
1.2 mMKH2PO4Potassium phosphate
7.81 mMNa2HPO4Disodium phosphate
3.19 mMNaH2PO4Sodium phosphate
4.0 mMC6H12O6D-Glucose
1.4 mMCaCl2Calcium chloride
1.3 mMMgCl2Magnesium chloride
6.5 mMCH4N2OUrea
0.00615 mMHSAHuman Serum Albumine
0.0052 mMC27H46OCholesterol
2.4 mMC3H5NaO3Socium lactate
0.7 mMC5H10N2O3Glutamine

Details: Once all components were mixed together, the pH was adjusted by supplementing 1.6 microliters of 25% HCl to yield pH of 7.33.
GridModel: Quantifoil / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was homogenous.

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 200 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: 1.2 µm / Nominal magnification: 92000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.91 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.1 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 20772
CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION
FSC plot (resolution estimation)

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