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- PDB-9hgr: In vitro grown WT Alpha-Synuclein Fibrils -

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Basic information

Entry
Database: PDB / ID: 9hgr
TitleIn vitro grown WT Alpha-Synuclein Fibrils
ComponentsAlpha-synuclein
KeywordsPROTEIN FIBRIL / Alpha-Synuclein / G14R Mutation / Fibrils / Cryo-EM / Protein Aggregation / Amyloid Structure
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 / 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 / dopamine biosynthetic process / response to iron(II) ion / SNARE complex assembly / negative regulation of dopamine metabolic process / positive regulation of neurotransmitter secretion / regulation of macrophage activation / positive regulation of inositol phosphate biosynthetic process / regulation of norepinephrine uptake / negative regulation of microtubule polymerization / regulation of locomotion / synaptic vesicle transport / transporter regulator activity / synaptic vesicle priming / dopamine uptake involved in synaptic transmission / protein kinase inhibitor activity / regulation of dopamine secretion / negative regulation of thrombin-activated receptor signaling pathway / mitochondrial ATP synthesis coupled electron transport / dynein complex binding / positive regulation of receptor recycling / cuprous ion binding / nuclear outer membrane / response to magnesium ion / positive regulation of exocytosis / synaptic vesicle exocytosis / positive regulation of endocytosis / kinesin binding / synaptic vesicle endocytosis / enzyme inhibitor activity / cysteine-type endopeptidase inhibitor activity / regulation of presynapse assembly / response to type II interferon / negative regulation of serotonin uptake / alpha-tubulin binding / beta-tubulin binding / phospholipase binding / behavioral response to cocaine / supramolecular fiber organization / phospholipid metabolic process / cellular response to fibroblast growth factor stimulus / axon terminus / inclusion body / cellular response to epinephrine stimulus / Hsp70 protein binding / 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 / regulation of long-term neuronal synaptic plasticity / synapse organization / PKR-mediated signaling / protein destabilization / phospholipid binding / receptor internalization / tau protein binding / long-term synaptic potentiation / terminal bouton / positive regulation of inflammatory response / 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 / chemical synaptic transmission / amyloid fibril formation / molecular adaptor activity / negative regulation of neuron apoptotic process / mitochondrial outer membrane / oxidoreductase activity
Similarity search - Function
Synuclein / Alpha-synuclein / Synuclein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsSicking, K. / Al-Azzani, M. / Outeiro, T.F. / Fernandez-Busnadiego, R.
Funding support Germany, United States, 5items
OrganizationGrant numberCountry
German Research Foundation (DFG)EXC 2067/1-390729940 Germany
German Research Foundation (DFG)SFB1286 (B8) Germany
German Research Foundation (DFG)SFB1286 (A12) Germany
German Research Foundation (DFG)448415290 Germany
Michael J. Fox FoundationASAP-000282 United States
Citation
Journal: Mol Neurodegener / Year: 2025
Title: A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features.
Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / ...Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / Aishwarya Agarwal / Susana R Chaves / Claudio O Fernández / Ulf Dettmer / Janin Lautenschläger / Markus Zweckstetter / Rubén Fernández-Busnadiego / Alexander Zimprich / Tiago Fleming Outeiro /
Abstract: BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding ...BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation.
METHODS: A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing-whole exome sequencing (WES), and neuropathological ...METHODS: A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing-whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays.
RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA ...RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation.
CONCLUSIONS: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical ...CONCLUSIONS: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.
#1: Journal: medRxiv / Year: 2025
Title: A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features.
Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / ...Authors: Christof Brücke / Mohammed Al-Azzani / Nagendran Ramalingam / Maria Ramón / Rita L Sousa / Fiamma Buratti / Michael Zech / Kevin Sicking / Leslie Amaral / Ellen Gelpi / Aswathy Chandran / Aishwarya Agarwal / Susana R Chaves / Claudio O Fernández / Ulf Dettmer / Janin Lautenschläger / Markus Zweckstetter / Ruben Fernandez Busnadiego / Alexander Zimprich / Tiago Fleming Outeiro /
Abstract: BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for ...BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. , the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD.
AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological ...AIM AND METHODS: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays.
RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant ...RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation.
SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and ...SUMMARY: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies.
History
DepositionNov 20, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name
Revision 1.2Oct 8, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-synuclein
B: Alpha-synuclein


Theoretical massNumber of molelcules
Total (without water)28,9522
Polymers28,9522
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Alpha-synuclein / Non-A beta component of AD amyloid / Non-A4 component of amyloid precursor / NACP


Mass: 14476.108 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNCA, NACP, PARK1 / Production host: Escherichia coli (E. coli) / References: UniProt: P37840
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: WT Alpha-Synuclein / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 14.46 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 53142 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001962
ELECTRON MICROSCOPYf_angle_d0.3481298
ELECTRON MICROSCOPYf_dihedral_angle_d3.124140
ELECTRON MICROSCOPYf_chiral_restr0.049170
ELECTRON MICROSCOPYf_plane_restr0.001162

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