Premium
Delineation of the Core Aggregation Sequences of TDP‐43 C‐Terminal Fragment
Author(s) -
Saini Akash,
Chauhan Virander Singh
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100427
Subject(s) - frontotemporal lobar degeneration , peptide , ubiquitin , cleavage (geology) , mutant , cytoplasm , chemistry , inclusion bodies , amyotrophic lateral sclerosis , computational biology , biophysics , biology , microbiology and biotechnology , recombinant dna , biochemistry , frontotemporal dementia , gene , medicine , disease , dementia , paleontology , pathology , fracture (geology)
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.