Nuclear Tau, a Key Player in Neuronal DNA Protection

Zeyni Mansuroglu,Sandrine Humez,Audrey Sultan,Nicolas Sergeant,Séverine Bégard,Anne Loyens,Eliette Bonnefoy,Morvane Colin,Marie-Christine Galas,Fabrice Nesslany,Luc Buée,Daniel Marzin,Smail Talahari,Marie Violet

doi:10.1074/jbc.m110.199976

Abstract

Tau, a neuronal protein involved in neurodegenerative disorders such as Alzheimer disease, which is primarily described as a microtubule-associated protein, has also been observed in the nuclei of neuronal and non-neuronal cells. However, the function of the nuclear form of Tau in neurons has not yet been elucidated. In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wild-type and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. These results highlight a novel role for nuclear Tau as a key player in early stress response.

Highlights

In vitro studies have shown that purified Tau directly binds to polynucleotides with a preference toward AT-rich DNA compared with GC-rich DNA sequences
Oxidative Stress and Heat Stress Induce Nuclear Accumulation of Tau—Mild hyperthermia shares common mechanisms with oxidative stress such as that induced by exposure to H2O2 and reactive oxygen species production [24, 25]
Given that neuronal nuclear Tau has primarily been described under a dephosphorylated state, based on Tau1 labeling using an antibody [27], we examined whether oxidative stress or heat stress (HS) could modulate the cellular localization of Tau

Summary

Introduction

In vitro studies have shown that purified Tau directly binds to polynucleotides with a preference toward AT-rich DNA compared with GC-rich DNA sequences. Ever, contradictory in vitro results have shown a protective or deleterious role of Tau in DNA integrity [7,8,9]. A recent study reported chromosomal aberrations in fibroblasts and lymphocytes from patients carrying a Tau mutation [10]. The protection of genomic integrity is a major challenge for living cells that are continuously exposed to DNA-damaging injuries, especially in the brain. Whether endogenous Tau has the capacity to protect neuronal DNA in situ has remained an unanswered question. We aimed to investigate the potential protective effects of Tau against DNA damage in central neurons

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Conclusion