TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP
dc.contributor.author | Arseni, Diana | |
dc.contributor.author | Chen, Renren | |
dc.contributor.author | Murzin, Alexey G. | |
dc.contributor.author | Peak-Chew, Sew Y. | |
dc.contributor.author | Garringer, Holly J. | |
dc.contributor.author | Newell, Kathy L. | |
dc.contributor.author | Kametani, Fuyuki | |
dc.contributor.author | Robinson, Andrew C. | |
dc.contributor.author | Vidal, Ruben | |
dc.contributor.author | Ghetti, Bernardino | |
dc.contributor.author | Hasegawa, Masato | |
dc.contributor.author | Ryskeldi-Falcon, Benjamin | |
dc.contributor.department | Pathology and Laboratory Medicine, School of Medicine | |
dc.date.accessioned | 2024-03-01T10:12:51Z | |
dc.date.available | 2024-03-01T10:12:51Z | |
dc.date.issued | 2023 | |
dc.description.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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Arseni D, Chen R, Murzin AG, et al. TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature. 2023;620(7975):898-903. doi:10.1038/s41586-023-06405-w | |
dc.identifier.uri | https://hdl.handle.net/1805/38981 | |
dc.language.iso | en_US | |
dc.publisher | Springer Nature | |
dc.relation.isversionof | 10.1038/s41586-023-06405-w | |
dc.relation.journal | Nature | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | PMC | |
dc.subject | Citrullination | |
dc.subject | DNA-binding proteins | |
dc.subject | Frontotemporal dementia | |
dc.subject | Frontotemporal lobar degeneration | |
dc.title | TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP | |
dc.type | Article |