Zinc Binding Directly Regulates Tau Toxicity Independent of Tau Hyperphosphorylation

Tau hyperphosphorylation is thought to underlie tauopathy. Working in a Drosophila tauopathy model expressing a human Tau mutant (hTauR406W, or Tau∗), we show that zinc contributes to the development of Tau toxicity through two independent actions: by increasing Tau phosphorylation and, more significantly, by directly binding to Tau. Elimination of zinc binding through amino acid substitution of Cys residues has a minimal effect on phosphorylation levels yet essentially eliminates Tau toxicity. The toxicity of the zinc-binding-deficient mutant Tau∗ (Tau∗C2A) and overexpression of native Drosophila Tau, also lacking the corresponding zinc-binding Cys residues, are largely impervious to zinc concentration. Importantly, restoration of zinc-binding ability to Tau∗ by introduction of a zinc-binding residue (His) into the original Cys positions restores zinc-responsive toxicities in proportion to zinc-binding affinities. These results indicate zinc binding is a substantial contributor to tauopathy and have implications for therapy development. [Display omitted] •Zinc affects Tau conformation in vitro and toxicity in vivo•Zinc can affect Tau hyperphosphorylation•Zinc binding to Tau is critical for Tau toxicity•Tau depends on both zinc binding and hyperphosphorylation for toxicity Using a Drosophila tauopathy model, Huang et al. show that zinc is an important contributor to the development of Tau toxicity, mainly through direct Tau binding. Removal of Tau zinc-binding capacity has a minimal effect on phosphorylation yet essentially eliminates Tau toxicity. Restoring zinc binding to Tau restores toxicity in proportion to zinc binding. The results indicate that zinc binding is a substantial contributor to tauopathy and likely have implications for therapy development.