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.

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

“…In neuronal or non-neuronal cells, nuclear Tau has been widely detected using pan-Tau antibodies. Further studies using various antibodies directed against phospho-dependent Tau epitopes confirmed the predominantly hypophosphorylated form of Tau in cell nuclei (20,24,27,29,52). Using the Tau1 antibody directed against a non-phosphorylated epitope of Tau protein (serine 195-202), differences in the sub-nuclear localization of Tau have been observed between human and murine cells.…”

“…Going a step further, in primary neuronal cultures, endogenous hypophosphorylated nuclear Tau was shown to protect DNA integrity under oxidative and hyperthermic stress conditions (27). The DNA protective function of Tau has been validated in vivo in adult neurons in the brain of mouse submitted to hyperthermic stress and under physiological condition (29). Although Tau may protect DNA integrity through AT-rich minor groove binding (27), it does not preclude the involvement of Tau in the DNA damage response (29).…”

“…The DNA protective function of Tau has been validated in vivo in adult neurons in the brain of mouse submitted to hyperthermic stress and under physiological condition (29). Although Tau may protect DNA integrity through AT-rich minor groove binding (27), it does not preclude the involvement of Tau in the DNA damage response (29).…”

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

“…It is worth mentioning that a diffuse TUNEL-positive staining of the cytoplasm was only present after heating in AMF-treated tumors, reflecting an additional labeling of remarkably fragmented RNA (likely by the applied heat) due to the labeling of 3′-OH termini after the breakage of nucleic acids. 38 The sole AMF treatment has no impact on therapy outcome as it does not result in the unspecific heating of tissue, in particular, because much lower magnetic field amplitudes and frequencies are used compared to MRI. By reaching temperatures up to 50°C during the performed in vivo experiments, the observed remarkable tumor destruction in both heat-based treatments was hypothesized to be connected to the regulation and/or destruction of key proteins involved in apoptosis, cell survival, angiogenesis, and cell cycle.…”

2015: Which new directions for Alzheimer's disease?

“…The precision of tau role in DNA protection and RNA integrity under physiological conditions or under ROSproducing stress (Violet et al, 2014) provides clarification for a mechanistic model in which tau disturbance initiates an explanation for DNA damages observed in AD. Principally, tau is a phosphoprotein.…”