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STRUCTURE OF PATHOLOGICAL TDP-43 FILAMENTS IN ALS-FTLD
Abstract
Aims
The abnormal aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD). It is also common in other diseases, including Alzheimer's and Parkinson's. However, the structures of pathological aggregated TDP-43 are unknown.
Methods
We used electron cryo-microscopy (cryo-EM) to determine the structures of pathological aggregated TDP-43 extracted from the frontal and motor cortices of individuals that succumbed to ALS with FTLD.
Results
We found a conserved amyloid-like filament structure comprising a single protofilament. The ordered filament core is formed by residues 282 to 360 in the TDP-43 low-complexity domain, which adopt a novel double-spiral-shaped fold. The fold shows no similarity to those of TDP-43 filaments formed in vitro. Abundant glycine and neutral polar residues facilitate numerous turns that restrict β-strand length, resulting in the absence of β-sheet stacking associated with cross-β amyloid structure. An uneven distribution of these residues gives rise to structurally and chemically distinct filament surfaces. External densities adjacent to these surfaces suggest possible ligand binding sites.
Conclusions
This work enhances our understanding of the molecular pathogenesis of ALS and FTLD, revealing the formation of filaments that are structurally distinct from amyloid filaments in other neurodegenerative diseases. The structure of pathological TDP-43 filaments in ALS-FTLD informs the development of accurate disease models, as well as diagnostic and therapeutic agents.