title: Delineation of the core aggregation sequences of TDP-43 C-terminal fragment.
abstract: 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.
authors: Malaria Research Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
authors: Akash
authors: A
authors: Saini
authors: Virander Singh
authors: VS
authors: Chauhan
mesh_terms: D000595:Amino Acid Sequence; D052160:Benzothiazoles; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008027:Light; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012542:Scattering, Radiation; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D010455:Peptides; D011994:Recombinant Proteins; D013844:Thiazoles; C009462:thioflavin T