Contrasting Effects of Ferric and Ferrous Ions on Oligomerization and Droplet Formation of Tau: Implications in Tauopathies and Neurodegeneration

The dysregulation of metal homeostasis is reported to enhance the aggregation of tau, a key neuronal microtubuleassociated protein. Herein, we found that ferric (Fe3+) ions enhanced tau aggregation. Fe3+ and Al3+ induced tau aggregation while several trivalent metal ions such as Cr3+, La3+, and V3+ had no discernable effect on tau aggregation. Fe3+ reduced the critical concentration of tau required for the liquid-liquid phase separation (LLPS); however, Cr3+, La3+, and V3+ did not affect tau droplet formation. Dynamic light scattering, atomic force microscopic, and transmission electron microscopic analysis suggested that Fe3+ significantly increased the formation of tau oligomers and fibrils. In contrast, Fe3+ neither enhanced tau droplet formation nor increased the heparin-induced aggregation of tau. Using a tryptophan mutant (Y310W-tau) of tau, Fe2+ was found to bind to tau with four times higher affinity than Fe2+. Acrylamide quenching of the tryptophan fluorescence of Y310W-tau, 1-anilino-8-naphthalene sulfonate (ANS) fluorescence experiment, and far- UV circular dichroism analysis indicated that Fe3+ decreased the solvent exposure of the tryptophan residue, perturbed the hydrophobic surface arrangement, and disrupted the secondary structure of tau, respectively. The increase in the beta-sheet content and a subsequent decrease in the disordered content of tau due to the binding of Fe3+ may favor tau aggregation. Fe(3+)may enhance and stabilize the non-covalent interactions between disordered domains of tau molecules leading to tau aggregation. The data highlighted the relationship between the dysregulation of ferric ions and neurodegenerative disorders.

Automated summary

The dysregulation of ferric ions leads to enhanced aggregation of tau protein, with Fe3+ decreasing the critical concentration required for liquid-liquid phase separation of tau and significantly increasing the formation of tau oligomers and fibrils. Fe3+ binds to tau with higher affinity compared to Fe2+ and disrupts the secondary structure of tau, favoring tau aggregation by increasing beta-sheet content and decreasing disordered content. Fe3+ may enhance non-covalent interactions between disordered domains of tau molecules, ultimately leading to tau aggregation and pointing to a potential relationship between dysregulation of ferric ions and neurodegenerative disorders.