Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation.

ABSTRACT: 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.

SUBMITTER: Huang Y 

PROVIDER: S-EPMC4306234 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature