8CG3

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

Summary for 8CG3

• Entry DOI: 10.2210/pdb8cg3/pdb
• EMDB information: 16628
• Descriptor: TAR DNA-binding protein 43 (1 entity in total)
• Functional 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 source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 223923.71

Authors

Arseni, D.,Ryskeldi-Falcon, B. (deposition date: 2023-02-03, release date: 2023-08-02, Last modification date: 2023-08-30)

Primary citation

Arseni, D.,Chen, R.,Murzin, A.G.,Peak-Chew, S.Y.,Garringer, H.J.,Newell, K.L.,Kametani, F.,Robinson, A.C.,Vidal, R.,Ghetti, B.,Hasegawa, M.,Ryskeldi-Falcon, B.
TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.
Nature, 620:898-903, 2023

PubMed 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.

PubMed: 37532939
DOI: 10.1038/s41586-023-06405-w

Experimental method

ELECTRON MICROSCOPY (2.39 Å)