title: A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions.
abstract: Nucleic acid protection is a substantial challenge for neurons, which are continuously exposed to oxidative stress in the brain. Neurons require powerful mechanisms to protect DNA and RNA integrity and ensure their functionality and longevity. Beside its well known role in microtubule dynamics, we recently discovered that Tau is also a key nuclear player in the protection of neuronal genomic DNA integrity under reactive oxygen species (ROS)-inducing heat stress (HS) conditions in primary neuronal cultures. In this report, we analyzed the capacity of Tau to protect neuronal DNA integrity in vivo in adult mice under physiological and HS conditions. We designed an in vivo mouse model of hyperthermia/HS to induce a transient increase in ROS production in the brain. Comet and Terminal deoxyribonucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assays demonstrated that Tau protected genomic DNA in adult cortical and hippocampal neurons in vivo under physiological conditions in wild-type (WT) and Tau-deficient (KO-Tau) mice. HS increased DNA breaks in KO-Tau neurons. Notably, KO-Tau hippocampal neurons in the CA1 subfield restored DNA integrity after HS more weakly than the dentate gyrus (DG) neurons. The formation of phosphorylated histone H2AX foci, a double-strand break marker, was observed in KO-Tau neurons only after HS, indicating that Tau deletion did not trigger similar DNA damage under physiological or HS conditions. Moreover, genomic DNA and cytoplasmic and nuclear RNA integrity were altered under HS in hippocampal neurons exhibiting Tau deficiency, which suggests that Tau also modulates RNA metabolism. Our results suggest that Tau alterations lead to a loss of its nucleic acid safeguarding functions and participate in the accumulation of DNA and RNA oxidative damage observed in the Alzheimer's disease (AD) brain.
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Violet
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Delattre
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Meryem
authors.initials: M
authors.lastname: Tardivel
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sultan
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Chauderlier
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Caillierez
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille Lille, France.
authors.forename: Smail
authors.initials: S
authors.lastname: Talahari
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille Lille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Nesslany
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lefebvre
authors.affiliation: CNRS FRE 3235, Génétique Moléculaire et Défense Antivirale Paris, France.
authors.forename: Eliette
authors.initials: E
authors.lastname: Bonnefoy
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Inserm UMR837, Alzheimer and Tauopathies Lille, France ; Jean Pierre Aubert Research Centre, Faculté de Médecine-Pôle Recherche, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université Droıt et Santé de Lille, CHU-Lille Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
keywords: DNA damage; DNA repair; RNA damage; Tau; hyperthermia; oxidative stress; γ-H2AX