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

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 and Benjamin Ryskeldi-Falcon ()
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Diana Arseni: MRC Laboratory of Molecular Biology
Renren Chen: MRC Laboratory of Molecular Biology
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Sew Y. Peak-Chew: MRC Laboratory of Molecular Biology
Holly J. Garringer: Indiana University School of Medicine
Kathy L. Newell: Indiana University School of Medicine
Fuyuki Kametani: Tokyo Metropolitan Institute of Medical Science
Andrew C. Robinson: University of Manchester, Salford Royal Hospital
Ruben Vidal: Indiana University School of Medicine
Bernardino Ghetti: Indiana University School of Medicine
Masato Hasegawa: Tokyo Metropolitan Institute of Medical Science
Benjamin Ryskeldi-Falcon: MRC Laboratory of Molecular Biology

Nature, 2023, vol. 620, issue 7975, 898-903

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06405-w

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