Abstract |
The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration ( FTLD)1,2. It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro3,4. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.
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Authors | Diana Arseni, Masato Hasegawa, Alexey G Murzin, Fuyuki Kametani, Makoto Arai, Mari Yoshida, Benjamin Ryskeldi-Falcon |
Journal | Nature
(Nature)
Vol. 601
Issue 7891
Pg. 139-143
(01 2022)
ISSN: 1476-4687 [Electronic] England |
PMID | 34880495
(Publication Type: Case Reports, Journal Article)
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Copyright | © 2021. The Author(s), under exclusive licence to Springer Nature Limited. |
Chemical References |
- Amyloid beta-Peptides
- DNA-Binding Proteins
- TARDBP protein, human
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Topics |
- Amino Acid Sequence
- Amyloid beta-Peptides
(metabolism)
- Amyotrophic Lateral Sclerosis
(metabolism, pathology)
- Cryoelectron Microscopy
- DNA-Binding Proteins
(chemistry, genetics, metabolism, ultrastructure)
- Female
- Frontal Lobe
(metabolism, pathology, ultrastructure)
- Frontotemporal Lobar Degeneration
(metabolism, pathology)
- Humans
- Male
- Middle Aged
- Motor Cortex
(metabolism, pathology, ultrastructure)
- Mutation
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