Zinc Binding Directly Regulates Tau Toxicity Independent of Tau Hyperphosphorylation

Yunpeng Huang,Zhihao Wu,Yu Cao,Minglin Lang,Bingwei Lu,Bing Zhou

doi:10.1016/j.celrep.2014.06.047

Abstract

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.

Highlights

Tau protein aggregation is found in several types of neurodegenerative diseases collectively termed “tauopathy,” which includes Alzheimer’s disease (AD), frontotemporal lobar degeneration chromosome 17, Pick’s disease, corticobasal degeneration, and the progressive supranuclear palsy (Brunden et al, 2009; Iqbal et al, 2005)
To investigate possible connections between metal genes and tauopathy, we set up a genetic screen to examine their interactions via a Drosophila tauopathy model using the bipartite upstream activating sequence (UAS)/Gal4 system
But not genes related to other metals, were found to present consistent rescuing or enhancing effects, suggesting they act as the modifiers of Drosophila tauopathy

Summary

Introduction

Tau protein aggregation is found in several types of neurodegenerative diseases collectively termed “tauopathy,” which includes Alzheimer’s disease (AD), frontotemporal lobar degeneration chromosome 17, Pick’s disease, corticobasal degeneration, and the progressive supranuclear palsy (Brunden et al, 2009; Iqbal et al, 2005). Tau is a microtubule-associated protein that can bind to microtubules and regulate their dynamics. Tau exhibits low levels of phosphorylation (Buée et al, 2000); it is hyperphosphorylated in several disease states. The abnormally hyperphosphorylated state of Tau protein can cause it to dissociate from the microtubule and aggregate into paired helical filaments (PHFs) (Kuret et al, 2005; Mazanetz and Fischer, 2007), leading to multiple downstream events and culminating in neuronal cell death (von Bergen et al, 2005). Because a detailed mechanism for Tau toxicity remains elusive, designing effective therapies for tauopathies continues to be a challenge

Results

Discussion

Conclusion