(515b) Simulations Uncovering the Role of Disease Related Mutants in TDP-43 Self-Assembled Fibrils

Brain deposits of amyloid-like aggregates containing the low complexity domain of TDP-43 are associated with amyotrophic lateral sclerosis and other neurodegenerative diseases. This domain contains most disease-related mutation sites and is considered to drive the aggregation process. The relatively recent release of self-assembled fibrils formed within this domain provided impetus for delineating the role of disease-related mutations. Here, we used MD simulations to refine the structure of TDP-43, and additionally investigate a series of TDP-43 mutant fibrils in comparison with the wild-type self-assembled structure. Our studies focus on fundamental biophysical structural and thermodynamic properties of the simulated systems, and provide atomic detail insights into the role of different disease-related mutants in relation to the folding and stability of the self-assembled system. Overall, our analysis sheds light in mutations which were previously considered to have a disputed role with regard to their effect on the fibril’s structure, and importantly, demonstrate and confirm the hypothesis that disease-prone mutations appear to thermodynamically favor, as well as promote the stabilization of the self-assembled structures, in line with experiments. Our studies broaden our understanding on TDP-43 disease-related mechanisms, and could provide a basis for future studies predicting possible disease-related mutants.