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- EMDB-70295: Cryo-EM structure of alpha-synuclein filaments derived from the f... -

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Basic information

Entry
Database: EMDB / ID: EMD-70295
TitleCryo-EM structure of alpha-synuclein filaments derived from the frontal cortex of the case of atypical multiple system atrophy
Map datamasked map
Sample
  • Complex: Asymmetric homodimer filament of alpha-synuclein
    • Complex: Asymmetric homodimer filament of alpha-synuclein
      • Protein or peptide: Alpha-synuclein
    • Complex: Unidentified protein that aggregated with the filament
      • Protein or peptide: Unidentified protein
Keywordshomo-dimer / asymmetric / filaments / multiple system atrophy / Lewy body dementia / 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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization ...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 / positive regulation of SNARE complex assembly / positive regulation of hydrogen peroxide catabolic process / supramolecular fiber / mitochondrial membrane organization / regulation of synaptic vesicle recycling / negative regulation of chaperone-mediated autophagy / regulation of reactive oxygen species biosynthetic process / negative regulation of platelet-derived growth factor receptor signaling pathway / positive regulation of protein localization to cell periphery / negative regulation of exocytosis / regulation of glutamate secretion / response to iron(II) ion / SNARE complex assembly / positive regulation of neurotransmitter secretion / dopamine biosynthetic process / regulation of norepinephrine uptake / transporter regulator activity / regulation of locomotion / mitochondrial ATP synthesis coupled electron transport / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / synaptic vesicle priming / negative regulation of microtubule polymerization / synaptic vesicle transport / positive regulation of receptor recycling / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / dynein complex binding / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / cuprous ion binding / positive regulation of exocytosis / response to magnesium ion / synaptic vesicle exocytosis / enzyme inhibitor activity / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / cysteine-type endopeptidase inhibitor activity / negative regulation of serotonin uptake / regulation of presynapse assembly / response to type II interferon / alpha-tubulin binding / supramolecular fiber organization / inclusion body / phospholipid metabolic process / cellular response to copper ion / axon terminus / cellular response to epinephrine stimulus / Hsp70 protein binding / response to interleukin-1 / regulation of microtubule cytoskeleton organization / SNARE binding / positive regulation of release of sequestered calcium ion into cytosol / adult locomotory behavior / negative regulation of protein kinase activity / excitatory postsynaptic potential / fatty acid metabolic process / phosphoprotein binding / protein tetramerization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / synapse organization / ferrous iron binding / protein destabilization / PKR-mediated signaling / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / positive regulation of inflammatory response / synaptic vesicle membrane / actin cytoskeleton / actin binding / growth cone / cell cortex / cellular response to oxidative stress / neuron apoptotic process / chemical synaptic transmission / molecular adaptor activity / negative regulation of neuron apoptotic process / response to lipopolysaccharide / histone binding / amyloid fibril formation / lysosome / oxidoreductase activity / transcription cis-regulatory region binding / postsynapse / positive regulation of apoptotic process / Amyloid fiber formation / copper ion binding / response to xenobiotic stimulus / axon / neuronal cell body
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsEnomoto M / Martinez-Valbuena I / Forrest SL / Xu X / Munhoz R / Li J / Rogaeva E / Lang AE / Kovacs GG
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA) United States
CitationJournal: Commun Biol / Year: 2025
Title: Lewy-MSA hybrid fold drives distinct neuronal α-synuclein pathology.
Authors: Masahiro Enomoto / Ivan Martinez-Valbuena / Shelley L Forrest / Xiaoxiao Xu / Renato P Munhoz / Jun Li / Ekaterina Rogaeva / Anthony E Lang / Gabor G Kovacs /
Abstract: The ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system ...The ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system atrophy (MSA), predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that the structures of α-synuclein filaments from LBD differ from MSA and juvenile-onset synucleinopathy (JOS). The rare atypical MSA subtype shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that α-synuclein can form a Lewy-MSA hybrid fold, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs), and conformational stability assays (CSA), are also linked to cytopathological differences. We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.
History
DepositionApr 23, 2025-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70295.png

Downloads & links

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Map

FileDownload / File: emd_70295.map.gz / Format: CCP4 / Size: 169.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmasked map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 354 pix.
= 329.22 Å		0.93 Å/pix.
x 354 pix.
= 329.22 Å		0.93 Å/pix.
x 354 pix.
= 329.22 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0085
Minimum - Maximum-0.03605036 - 0.071073994
Average (Standard dev.)0.000043081087 (±0.0014156043)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions354354354
Spacing354354354
CellA=B=C: 329.22 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap2

Fileemd_70295_half_map_1.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap1

Fileemd_70295_half_map_2.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Asymmetric homodimer filament of alpha-synuclein

EntireName: Asymmetric homodimer filament of alpha-synuclein
Components
  • Complex: Asymmetric homodimer filament of alpha-synuclein
    • Complex: Asymmetric homodimer filament of alpha-synuclein
      • Protein or peptide: Alpha-synuclein
    • Complex: Unidentified protein that aggregated with the filament
      • Protein or peptide: Unidentified protein

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Supramolecule #1: Asymmetric homodimer filament of alpha-synuclein

SupramoleculeName: Asymmetric homodimer filament of alpha-synuclein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Asymmetric homodimer filament of alpha-synuclein

SupramoleculeName: Asymmetric homodimer filament of alpha-synuclein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1

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Supramolecule #3: Unidentified protein that aggregated with the filament

SupramoleculeName: Unidentified protein that aggregated with the filament
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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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: 14.476108 KDa
SequenceString:
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK EQVTNVGGAV VTGVTAVAQK TVEGAGSIA AATGFVKKDQ LGKNEEGAPQ EGILEDMPVD PDNEAYEMPS EEGYQDYEPE A

UniProtKB: Alpha-synuclein

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Macromolecule #2: Unidentified protein

MacromoleculeName: Unidentified protein / type: protein_or_peptide / ID: 2 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 443.539 Da
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.75 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.38 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 67027
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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