EMDB-16677: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 1)

Basic information

Entry

Database: EMDB / ID: EMD-16677

• Title: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 1)

Sample

• Tissue: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP

• Keywords: TDP-43 / FTD / FTLD / amyloid / filaments / fibril / neurodegeneration / neurodegenerative disease / RBP / RNA-binding protein / LCD / low-complexity domain / frontotemporal dementia / frontotemporal lobar degeneration / pathological / RNA BINDING PROTEIN / PROTEIN FIBRIL
• Biological species: Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 2.65 Å
• Authors: Arseni D / Ryskeldi-Falcon B

Funding support

United Kingdom, 1 items

Organization	Grant number	Country
Medical Research Council (MRC, United Kingdom)	MC_UP_1201/25	United Kingdom

• Citation: Journal: Nature / Year: 2023; Title: TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.; Authors: Diana Arseni / Renren Chen / Alexey G Murzin / Sew Y Peak-Chew / Holly J Garringer / Kathy L Newell / Fuyuki Kametani / Andrew C Robinson / Ruben Vidal / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon / ; Abstract: The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD). A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.

History

Deposition	Feb 9, 2023	-
Header (metadata) release	Aug 16, 2023	-
Map release	Aug 16, 2023	-
Update	Aug 30, 2023	-
Current status	Aug 30, 2023	Processing site: PDBe / Status: Released

Map

• File: Download / File: emd_16677.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Voxel size: X=Y=Z: 0.86 Å

Density

Contour Level	By AUTHOR: 0.013
Minimum - Maximum	-0.032069974 - 0.0602319
Average (Standard dev.)	0.0003228588 (±0.0031546238)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 256 256 256 Spacing 256 256 256
Cell	A=B=C: 220.16 Å α=β=γ: 90.0 °

Supplemental data

Mask #1

• File: emd_16677_msk_1.map

Half map: #1

• File: emd_16677_half_map_1.map

Half map: #2

• File: emd_16677_half_map_2.map

Sample components

Entire : TDP-43 amyloid filaments extracted from the frontal cortex of an ...

• Entire: Name: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP

Components

• Tissue: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP

Supramolecule #1: TDP-43 amyloid filaments extracted from the frontal cortex of an ...

• Supramolecule: Name: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP; type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1
• Source (natural): Organism: Homo sapiens (human) / Tissue: Brain

Experimental details

Structure determination

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

Sample preparation

• Buffer: pH: 7.4
• Vitrification: Cryogen name: ETHANE

Electron microscopy

• Microscope: FEI TITAN KRIOS
• Image recording: Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 35.896 e/Ų
• Electron beam: Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
• Electron optics: Illumination 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

Image processing

• Final reconstruction: Applied symmetry - Helical parameters - Δz: 1.175 Å; Applied symmetry - Helical parameters - Δ&Phi: 4.99 °; Applied symmetry - Helical parameters - Axial symmetry: C₁ (asymmetric); Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 100937
• Startup model: Type of model: NONE
• Final angle assignment: Type: NOT APPLICABLE