Post-Translational Modifications Control Phase Transitions of Tau

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Tau protein self-assembly into paired helical filaments (PHFs) is a hallmark of Alzheimer's disease (AD) pathology.
• The influence of AD-specific post-translational modifications (PTMs) on Tau assembly into PHFs remains incompletely understood.

Purpose of the Study:

• To investigate the impact of key AD-associated PTMs on the in vitro assembly of Tau.
• To elucidate the role of specific PTMs in Tau nucleation and aggregation kinetics.

Main Methods:

• Synthetic production of Tau(291-391) with N-acetyllysine, phosphoserine, phosphotyrosine, and N-glycosylation.
• Utilized electron and optical microscopy techniques to analyze Tau assembly.
• Assessed Tau aggregation and liquid-liquid phase separation (LLPS) under various conditions (cofactor-free, heparin-induced, RNA-mediated).

Main Results:

• AD-specific PTMs generally inhibited in vitro Tau assembly into PHFs.
• Phosphorylation uniformly mitigated Tau aggregation and LLPS.
• Acetylation exhibited variable effects, either promoting or inhibiting phase transitions depending on the aggregation context.
• PTMs outside the Tau core region were critical for PHF nucleation.

Conclusions:

• Site-specific PTMs and environmental factors intricately modulate Tau aggregation kinetics.
• PTMs, particularly those distal to the core, play a pivotal role in regulating Tau self-assembly and PHF formation.
• Understanding PTMs' influence is crucial for deciphering Tau's role in AD pathogenesis.