Pathological C-terminal phosphomimetic substitutions alter the mechanism of liquid-liquid phase separation of TDP-43 low complexity domain.

Proteinaceous inclusions composed of phosphorylated, C-terminal TDP-43 fragments have long been recognized as hallmarks of several neurodegenerative diseases, in particular amyotrophic lateral sclerosis and frontotemporal dementia. A rapidly growing number of studies indicate that these proteinopathies may be closely related to liquid-liquid phased separation (LLPS) of TDP-43, but the impact of phosphorylation on TDP-43 LLPS remains largely unexplored. In this study we used a combination of experimental methods and coarse-grained simulations to ascertain, in mechanistic terms, how phosphorylation at pathologically-critical C-terminal sites impacts liquid-liquid phase separation of the low complexity domain of TDP-43. Our results broaden our understanding of the mechanisms driving pathogenic process in these neurodegenerative diseases.