14-3-3/Tau molecular glues modulate in vitro tau condensation.

The intrinsically disordered protein Tau is highly phosphorylated under pathological conditions, which, among others, results in Tau liquid-liquid phase separation (LLPS), followed by aggregation. The hub protein 14-3-3 regulates Tau protein solubility and prevents LLPS by binding with phosphorylated Tau residues pS214 and pS324. Here, we report the stabilization of this Tau/14-3-3 protein-protein interaction (PPI) using reversible-covalent small-molecule molecular glues. By strengthening the 14-3-3/Tau interaction the molecular glues enhance the effect of 14-3-3 on Tau solubility in LLPS. This demonstrates the potential of modulating the 14-3-3/Tau PPI for novel drug discovery efforts in neurodegenerative diseases.