Structure of pathological TDP-43 filaments from ALS with FTLD

The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia isthe defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)(1,2).1t is also common in other diseases, includingAlzheimer's and Parkinson's. No disease-modifying therapies exist forthese 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 vitro(3,4). An abundance of glycine and neutral polar residues facilitates numerousturns and restricts beta-strand length, which results in an absence of beta-sheet stackingthat is associated with cross-beta-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 ofALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.

Automated summary

Abnormal aggregation of TDP-43 is a defining pathological hallmark in ALS and FTLD, as well as in other diseases. Cryo-electron microscopy revealed an amyloid-like filament structure comprising a single protofilament with a unique double-spiral-shaped fold in aggregated TDP-43, different from in vitro-formed filaments. The presence of glycine and neutral polar residues facilitates numerous turns and restricts beta-strand length, resulting in an absence of beta-sheet stacking and unique ligand-binding site possibilities. These findings enhance our understanding of ALS and FTLD molecular pathogenesis and inform the development of diagnostic and therapeutic agents targeting aggregated TDP-43.