Fig. 1. Schematic representation of the structure and aggregation-associated mutations of TDP-43.

The TDP-43 protein contains a nuclear localization signal (NLS), 2 RNA-recognition motifs (RRM1 and RRM2), a nuclear export sequence (NES), and a glycine-rich region (GRR). Numerous disease-associated TDP-43 mutations have been identified in the GRR. Most disease-associated TDP-43 missense mutations have been identified to accelerate TDP-43 aggregation.