Delineation of the Core Aggregation Sequences of TDP‐43 C‐Terminal Fragment

Ubiquitinated cytoplasmic inclusions of TDP-43 and its C-terminal cleavage products are the pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions. The C-terminal fragments (CTFs) of TDP-43 are increasingly considered to play an important role in its aggregation and in disease. Here, we employed a set of synthetic peptides spanning the length of the TDP-43 CTF (220-414) in order to find out its core aggregation domains. Two regions, one in the RRM-2 domain (246-255) and the other in the C-terminal domain (311-320) of TDP-43, stand out as highly aggregation prone. Studies done on recombinant purified TDP-43 CTF and its three mutants, in which these sequences were deleted individually and together, suggested that the 311-320 region has a more crucial role to play than the 246-255 in its aggregation. The study helps in defining specific peptide sequences that might form the core of TDP-43 aggregation. Identification of these sequences could help in designing peptide based inhibitors of TDP-43 aggregation.