title: 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.
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yunpeng
authors: Y
authors: Huang
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Zhihao
authors: Z
authors: Wu
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yu
authors: Y
authors: Cao
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Minglin
authors: M
authors: Lang
authors: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Bingwei
authors: B
authors: Lu
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: zhoubing@mail.tsinghua.edu.cn.
authors: Bing
authors: B
authors: Zhou
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D011485:Protein Binding; D024801:Tauopathies / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D006639:Histidine; D015032:Zinc; D003545:Cysteine