Movie
Controller
Structure viewers
About Yorodumi Papers
+Search query
-Structure paper
| Title | TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. |
|---|---|
| Journal, issue, pages | Nature, Vol. 620, Issue 7975, Page 898-903, Year 2023 |
| Publish date | Aug 2, 2023 |
 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 /    |
| 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 ...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. |
 External links | Nature / PubMed:37532939 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 2.39 - 2.93 Å |
| Structure data | EMDB-16628, PDB-8cg3: EMDB-16642, PDB-8cgg: EMDB-16643, PDB-8cgh:  EMDB-16677: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 1)  EMDB-16681: Structure of TDP-43 amyloid filaments from type A FTLD-TDP (individual 2, variant 2)  EMDB-16682: Structure of TDP-43 amyloid filaments from type A FTLD-TDP (individual 3, variant 1) |
| Source |
|
 Keywords | PROTEIN FIBRIL /  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 |
