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- EMDB-45979: Cryo-EM filament structure in FTLD-synuclein -

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Basic information

Entry
Database: EMDB / ID: EMD-45979
TitleCryo-EM filament structure in FTLD-synuclein
Map data
Sample
  • Complex: Alpha-synuclein filaments extracted from the human brain with multiple system atrophy
    • Protein or peptide: Alpha-synuclein
  • Ligand: water
Keywordsamyloid / filament / synuclein / human brain / cryo-EM / fibril / MSA / FTLD / PROTEIN FIBRIL
Function / homology
Function and homology information


negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 ...negative regulation of mitochondrial electron transport, NADH to ubiquinone / 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 / 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 thrombin-activated receptor signaling pathway / negative regulation of microtubule polymerization / synaptic vesicle priming / synaptic vesicle transport / Lewy body / synaptic vesicle exocytosis / regulation of norepinephrine uptake / transporter regulator activity / positive regulation of inositol phosphate biosynthetic process / protein kinase inhibitor activity / regulation of dopamine secretion / positive regulation of receptor recycling / cuprous ion binding / positive regulation of exocytosis / nuclear outer membrane / dynein complex binding / synaptic transmission, dopaminergic / response to magnesium ion / positive regulation of endocytosis / negative regulation of serotonin uptake / cysteine-type endopeptidase inhibitor activity / kinesin binding / regulation of presynapse assembly / synaptic vesicle endocytosis / alpha-tubulin binding / beta-tubulin binding / behavioral response to cocaine / phospholipase binding / 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 / positive regulation of release of sequestered calcium ion into cytosol / cellular response to copper ion / axon terminus / enzyme inhibitor activity / glutathione metabolic process / SNARE binding / protein tetramerization / protein sequestering activity / regulation of microtubule cytoskeleton organization / receptor internalization / phosphoprotein binding / microglial cell activation / protein destabilization / tubulin binding / ferrous iron binding / synapse organization / phospholipid binding / PKR-mediated signaling / tau protein binding / enzyme activator activity / positive regulation of inflammatory response / terminal bouton / actin cytoskeleton / synaptic vesicle membrane / negative regulation of neuron apoptotic process / response to lipopolysaccharide / growth cone / actin binding / cellular response to oxidative stress / cell cortex / histone binding / microtubule binding / amyloid fibril formation / mitochondrial outer membrane / lysosome / oxidoreductase activity / mitochondrial inner membrane / transcription cis-regulatory region binding / positive regulation of apoptotic process / ribosome / mitochondrial matrix / Amyloid fiber formation / copper ion binding / protein domain specific binding / axon / neuronal cell body / calcium ion binding
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang Y / Scheres HWS / Goedert M
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
CitationJournal: Neuropathol Appl Neurobiol / Year: 2025
Title: Identical Seeding Characteristics and Cryo-EM Filament Structures in FTLD-Synuclein and Typical Multiple System Atrophy.
Authors: Patrick W Cullinane / Yang Yang / Viorica Chelban / Yee Yen Goh / Kirsten Ebanks / Toby Curless / Sarah Wrigley / Eduardo de Pablo-Fernández / Janice Holton / Sew Peak-Chew / Catarina ...Authors: Patrick W Cullinane / Yang Yang / Viorica Chelban / Yee Yen Goh / Kirsten Ebanks / Toby Curless / Sarah Wrigley / Eduardo de Pablo-Fernández / Janice Holton / Sew Peak-Chew / Catarina Franco / Amanda L Woerman / Henry Houlden / Thomas T Warner / Sjors H W Scheres / Michel Goedert / Zane Jaunmuktane /
Abstract: AIMS: The aim of this study is to identify the prevalence of frontotemporal dementia (FTD)/corticobasal syndrome (CBS) in a large cohort of pathologically confirmed cases of multiple system atrophy ...AIMS: The aim of this study is to identify the prevalence of frontotemporal dementia (FTD)/corticobasal syndrome (CBS) in a large cohort of pathologically confirmed cases of multiple system atrophy (MSA) and to determine the α-synuclein seeding characteristics and electron cryo-microscopy (cryo-EM) filament structure in frontotemporal lobar degeneration with MSA-type α-synuclein pathology (FTLD-synuclein).
METHODS: The archives of the Queen Square Brain Bank (1989-2023) were searched for histologically confirmed MSA cases, and those with a clinical diagnosis of FTD/CBS were reviewed for pathological ...METHODS: The archives of the Queen Square Brain Bank (1989-2023) were searched for histologically confirmed MSA cases, and those with a clinical diagnosis of FTD/CBS were reviewed for pathological features of FTLD-synuclein. Phosphotungstic acid (PTA)-precipitated brain homogenates from FTLD-synuclein, dementia with Lewy bodies (DLB) and G51D SNCA synucleinopathy cases were used to seed aggregation in α-syn140*A53T-YFP HEK293T cells. The structure of α-synuclein filaments from an FTLD-synuclein case was determined by cryo-EM.
RESULTS: We identified 283 cases of MSA. Four cases had a clinical diagnosis of CBS, one of which met pathological criteria for FTLD-synuclein. Genetic studies in this case were negative for SNCA ...RESULTS: We identified 283 cases of MSA. Four cases had a clinical diagnosis of CBS, one of which met pathological criteria for FTLD-synuclein. Genetic studies in this case were negative for SNCA variants, and PTA-precipitated brain homogenates seeded abundant cytoplasmic α-synuclein inclusions that were morphologically indistinguishable from those of typical MSA but distinct from those of G51D SNCA and DLB. MSA Type II α-synuclein filaments were identified by cryo-EM.
CONCLUSIONS: FTD/CBS is rarely associated with MSA pathology. The cell seeding characteristics and cryo-EM findings support the classification of FTLD-synuclein as a subtype of MSA, differentiating ...CONCLUSIONS: FTD/CBS is rarely associated with MSA pathology. The cell seeding characteristics and cryo-EM findings support the classification of FTLD-synuclein as a subtype of MSA, differentiating it from genetic synucleinopathies, such as those with SNCA variants G51D and A53E, which have neuropathological features overlapping with MSA and Lewy body diseases. These cases expand the clinicopathological spectrum of MSA and FTLD and have implications for our understanding of selective neuronal vulnerability in MSA and the interpretation of α-synuclein biomarker studies.
History
DepositionJul 30, 2024-
Header (metadata) releaseAug 14, 2024-
Map releaseAug 14, 2024-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45979.png

Downloads & links

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Map

FileDownload / File: emd_45979.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
7.05 Å/pix.
x 60 pix.
= 423. Å		7.05 Å/pix.
x 60 pix.
= 423. Å		7.05 Å/pix.
x 60 pix.
= 423. Å

Surface

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Images are generated by Spider.

Voxel size
XYZ
EMDB info.0.730.730.73
CCP4 map header7.057.057.05
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.018614734 - 0.033973172
Average (Standard dev.)0.0001617896 (±0.001911425)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 233.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45979_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Sample components

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Entire : Alpha-synuclein filaments extracted from the human brain with mul...

EntireName: Alpha-synuclein filaments extracted from the human brain with multiple system atrophy
Components
  • Complex: Alpha-synuclein filaments extracted from the human brain with multiple system atrophy
    • Protein or peptide: Alpha-synuclein
  • Ligand: water

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Supramolecule #1: Alpha-synuclein filaments extracted from the human brain with mul...

SupramoleculeName: Alpha-synuclein filaments extracted from the human brain with multiple system atrophy
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-synuclein

MacromoleculeName: Alpha-synuclein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / 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: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 5 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 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: 4.85 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.43 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 195773
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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