Zinc Binding Directly Regulates Tau Toxicity Independent of Tau Hyperphosphorylation

• 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

SummaryTau 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.

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