Post-Translational Modifications Control Phase Transitions of Tau

assembly of Tau into PHFs. Interestingly, while acetylation's effect on Tau assembly displayed variability, either promoting or inhibiting phase transitions in cofactor-free aggregation, heparin-induced aggregation, and RNA-mediated liquid-liquid phase separation (LLPS), phosphorylation uniformly mitigated these processes. Our observations suggest that PTMs, particularly those situated outside the rigid core, are pivotal in the nucleation of PHFs. Moreover, with heparin-induced aggregation leading to the formation of heterogeneous aggregates, most AD-specific PTMs appeared to decelerate aggregation. The impact of acetylation on RNA-induced LLPS was notably site-dependent, whereas phosphorylation consistently reduced LLPS across all proteoforms examined. These insights underscore the complex interplay between site-specific PTMs and environmental factors in modulating Tau aggregation kinetics, highlighting the role of PTMs located outside the ordered filament core in driving the self-assembly.