EMDB-45007: Straight Filament of tau amyloids found in Down Syndrome individuals

Basic information

Entry

Database: EMDB / ID: EMD-45007

• Title: Straight Filament of tau amyloids found in Down Syndrome individuals

Sample

• Tissue: Straight Filaments purified from Down Syndrome individual brain tissue
  • Protein or peptide: Microtubule-associated protein tau

• Keywords: Amyloid / filament / neurodegeneration / Down syndrome / PROTEIN FIBRIL

Function / homology

Function:

plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / axon development / axonal transport of mitochondrion / rRNA metabolic process / central nervous system neuron development / regulation of microtubule-based movement / regulation of mitochondrial fission / regulation of chromosome organization / intracellular distribution of mitochondria / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / regulation of calcium-mediated signaling / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / protein polymerization / positive regulation of microtubule polymerization / regulation of cellular response to heat / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / stress granule assembly / enzyme inhibitor activity / cellular response to reactive oxygen species / regulation of microtubule cytoskeleton organization / memory / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of synaptic plasticity / Hsp90 protein binding / SH3 domain binding / synapse organization / regulation of autophagy / protein homooligomerization / microtubule cytoskeleton organization / PKR-mediated signaling / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / learning or memory / protein-macromolecule adaptor activity / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus

Domain/homology:

Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile. / :

Component:

Microtubule-associated protein tau

• Biological species: Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 3.0 Å
• Authors: Tse E / Ghosh U / Condello C / Southworth D

Funding support

United States, 1 items

Organization	Grant number	Country
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)	RF1NS133651	United States

• Citation: Journal: Acta Neuropathol Commun / Year: 2024; Title: Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer's disease fold.; Authors: Ujjayini Ghosh / Eric Tse / Hyunjun Yang / Marie Shi / Christoffer D Caro / Feng Wang / Gregory E Merz / Stanley B Prusiner / Daniel R Southworth / Carlo Condello / ; Abstract: Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

History

Deposition	May 22, 2024	-
Header (metadata) release	Aug 14, 2024	-
Map release	Aug 14, 2024	-
Update	Aug 14, 2024	-
Current status	Aug 14, 2024	Processing site: RCSB / Status: Released

Map

• File: Download / File: emd_45007.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Voxel size: X=Y=Z: 0.834 Å

Density

Contour Level	By AUTHOR: 0.0139
Minimum - Maximum	-0.048938368 - 0.08984901
Average (Standard dev.)	0.000110066816 (±0.002721148)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 280 280 280 Spacing 280 280 280
Cell	A=B=C: 233.52 Å α=β=γ: 90.0 °

Supplemental data

Half map: #1

• File: emd_45007_half_map_1.map

Half map: #2

• File: emd_45007_half_map_2.map

Sample components

Entire : Straight Filaments purified from Down Syndrome individual brain tissue

• Entire: Name: Straight Filaments purified from Down Syndrome individual brain tissue

Components

• Tissue: Straight Filaments purified from Down Syndrome individual brain tissue
  • Protein or peptide: Microtubule-associated protein tau

Supramolecule #1: Straight Filaments purified from Down Syndrome individual brain tissue

• Supramolecule: Name: Straight Filaments purified from Down Syndrome individual brain tissue; type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
• Source (natural): Organism: Homo sapiens (human)

Macromolecule #1: Microtubule-associated protein tau

• Macromolecule: Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
• Source (natural): Organism: Homo sapiens (human)
• Molecular weight: Theoretical: 8.370578 KDa

Sequence

String:

GSVQIVYKPV DLSKVTSKCG SLGNIHHKPG GGQVEVKSEK LDFKDRVQSK IGSLDNITHV PGGGNKKIET HKLTFRE

UniProtKB: Microtubule-associated protein tau

Experimental details

Structure determination

• Method: cryo EM
• Processing: helical reconstruction
• Aggregation state: filament

Sample preparation

• Buffer: pH: 7.4
• Vitrification: Cryogen name: ETHANE
• Details: Sarkosyl extraction of insoluble tau from fresh-frozen frontal cortex samples from Down Syndrome individuals

Electron microscopy

• Microscope: FEI TITAN KRIOS
• Specialist optics: Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
• Image recording: Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 56.0 e/Ų
• Electron beam: Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
• Electron optics: C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
• Experimental equipment: Model: Titan Krios / Image courtesy: FEI Company

Image processing

• Final reconstruction: Applied symmetry - Helical parameters - Δz: 4.81 Å; Applied symmetry - Helical parameters - Δ&Phi: -1.08 °; Applied symmetry - Helical parameters - Axial symmetry: C₁ (asymmetric); Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 47801
• Startup model: Type of model: INSILICO MODEL / In silico model: relion_helix_inimodel2d; Details: selected class averages with similar views along filament length
• Final angle assignment: Type: NOT APPLICABLE