Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structure of pathological TDP-43 filaments from ALS with FTLD.
Journal, issue, pages	Nature, Vol. 601, Issue 7891, Page 139-143, Year 2022
Publish date	Dec 8, 2021
Authors	Diana Arseni / Masato Hasegawa / Alexey G Murzin / Fuyuki Kametani / Makoto Arai / Mari Yoshida / Benjamin Ryskeldi-Falcon /
PubMed Abstract	The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) ...The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD). It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.
External links	Nature / PubMed:34880495 / PubMed Central
Methods	EM (helical sym.)
Resolution	2.59 - 2.94 Å
Structure data	13708 7py2 EMDB-13708, PDB-7py2: Structure of pathological TDP-43 filaments from ALS with FTLD Method: EM (helical sym.) / Resolution: 2.59 Å EMDB-13710: Structure of pathological TDP-43 filaments from ALS with FTLD (Individual 1, motor cortex) Method: EM (helical sym.) / Resolution: 2.94 Å EMDB-13712: Structure of pathological TDP-43 filaments from ALS with FTLD (Individual 2, frontal cortex). Method: EM (helical sym.) / Resolution: 2.83 Å
Source	homo sapiens (human)
Keywords	PROTEIN FIBRIL / TDP-43 / ALS / amyotrophic lateral sclerosis / FTD / frontotemporal dementia / FTLD / frontotemporal lobar degeneration / amyloid / filament / fibril / neurodegenerative / neurodegeneration