Novel insights into the structural changes induced by disease-associated mutations in TDP-43: a computational approach

Over the last two decades, the pathogenic aggregation of TAR DNA-binding protein 43 (TDP-43) is found to be strongly associated with several fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD), etc. While the mutations and truncation in TDP-43 protein have been suggested to be responsible for TDP-43 pathogenesis by accelerating the aggregation process, the effects of these mutations on the bio-mechanism of pathological TDP-43 protein remained poorly understood. Investigating this at the molecular level, we formulized an integrated workflow of molecular dynamic simulation and machine learning models (MD-ML). By performing an extensive structural analysis of three disease-related mutations (i.e., I168A, D169G, and I168A-D169G) in the conserved RNA recognition motifs (RRM1) of TDP-43, we observed that the I168A-D169G double mutant delineates the highest packing of the protein inner core as compared to the other mutations, which may indicate more stability and higher chances of pathogenesis. Moreover, through our MD-ML workflow, we identified the biological descriptors of TDP-43 which includes the interacting residue pairs and individual protein residues that influence the stability of the protein and could be experimentally evaluated to develop potential therapeutic strategies.Communicated by Ramaswamy H. Sarma.