TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP.

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)1,2. 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 FTLD3-7. 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 dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. 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.

• 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
• Journal: Nature (Nature) Vol. 620 Issue 7975 Pg. 898-903 (Aug 2023) ISSN: 1476-4687 [Electronic] England
• PMID: 37532939 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• DNA-Binding Proteins
• TARDBP protein, human

Topics

• Humans
• Citrullination
• Cryoelectron Microscopy
• DNA-Binding Proteins (chemistry, metabolism, ultrastructure)
• Frontotemporal Dementia (metabolism, pathology)
• Frontotemporal Lobar Degeneration (classification, metabolism, pathology)
• Methylation