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

Abstract

The dysregulation of metal homeostasis is reported to enhance the aggregation of tau, a key neuronal microtubule-associated 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, fe2+ neither enhanced tau droplet formation nor increased the heparin-induced aggregation of tau. Using a tryptophan mutant (y310w-tau) of tau, fe3+ 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 β-sheet content and a subsequent decrease in the disordered content of tau due to the binding of fe3+ may favor tau aggregation. Fe3+ 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. © 2021 american chemical society.