Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation.
Bottom Line: Tau hyperphosphorylation is thought to underlie tauopathy.Elimination of zinc binding through amino acid substitution of Cys residues has a minimal effect on phosphorylation levels yet essentially eliminates Tau toxicity.These results indicate zinc binding is a substantial contributor to tauopathy and have implications for therapy development.
Affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.Show MeSH
Related in: MedlinePlus
Mentions: If loss of toxicity for Tau*C2A is the result of loss of zinc binding, and for Tau*S2A from phosphorylation reduction, we expect the zinc responses of Tau*C2A, Tau*S2A, and Tau* flies to be different. Indeed, unlike that of Tau* and Tau*S2A flies, zinc could not appreciably affect the lifespan of Tau*C2A flies (Figure 5A). However, for similarly nontoxic Tau*S2A, which is able to bind zinc, zinc-responsiveness was still apparent (Figure 5A). Paraffin brain sections also revealed that zinc could not influence the toxicity of Tau*C2A: when treated with zinc, the neurodegeneration in Tau*C2A flies did not noticeably worsen as measured by the number of vacuoles formed in the brains (Figures 5B1 and 5B2).
Affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.