Emergence of Compact Oligomers inside the Small-World Network of TDP-43 Condensates.

Liquid-liquid phase separation (LLPS) of TDP-43 mediates the formation of pathological inclusions in various neurodegenerative diseases, with the condensate structures and related amyloid aggregation remaining elusive. Here, by developing a data-driven bottom-up coarse-grained model using discrete molecular dynamics simulations, we found proteins in the condensates of TDP-43 forming a dynamic network of fluctuating sizes. While dominated by peptides engaged with a small number of peptides connected by a low number of interpeptide contacts, the condensates also contained peptides with large numbers of connections, serving as hubs of a small-world network. Importantly, peptides in these high-contact states were intertwined to form oligomers that were stable for relatively long periods inside the weakly connected network. These oligomers were likely the aggregation intermediates toward nucleation of amyloid fibrils. Therefore, this transferable coarse-grained model may serve as a powerful tool for unraveling the inner workings of LLPS and amyloid aggregation.