Nuclear Tau, a Key Player in Neuronal DNA Protection

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 wildtype 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.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Even after maturation, low levels of Tau are present in other neuronal compartments, for example, the nucleus (Loomis et al 1990;Sultan et al 2011) and dendrites (Papasozomenos and Binder 1987), and in other brain cells, notably oligodendrocytes (Goldbaum et al 2003;LoPresti et al 1995). Moreover, Tau mRNA can be detected in many cell types (Gu et al 1996), even in muscle fibers where Tau forms aggregates in inclusion body myositis (Askanas and Engel 2008).…”

“…The significance in a cellular context is not clear at present, but micelles of arachidonic acid have been suggested as nucleators of Tau aggregation (Wilson and Binder 1997). Likewise, the interaction with nucleic acids was suggested from the observation of nuclear Tau (Loomis et al 1990); RNAs became interesting as potential nucleators of Tau aggregation (Kampers et al 1996), but insights into functions came recently with the discovery that Tau can protect DNA against heat and oxidative damage (Sultan et al 2011). Given Tau's versatile structure, one can expect that the list of interactors will surely grow; for further details we refer to Table 3.…”

“…An overall shift of phosphorylation potential can occur, for example, by a temperature drop during anesthesia or experimental diabetes, which reduces the activity of PP2a and thus mimics an Alzheimer-like phosphorylation state on Tau, reminiscent of the effects of aging (Planel et al 2007a;Planel et al 2007b;Veeranna et al 2009). Conversely, heat stress and oxidative stress activate PP2a and thus generate a low state of Tau phoshorylation, which protects against DNA damage (Davis et al 1997;Sultan et al 2011). Therefore, efforts are underway to develop treatments for AD by reducing Tau phosphorylation, either by inhibiting key kinases (e.g., Ahn et al 2005;Seabrook et al 2007) or by activating phosphatases such as PP2a (Tanimukai et al 2005).…”

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.…”

“…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. In human brain and interphase non-neuronal cells, the Tau1 antibody detects a unique nucleolar localization of Tau (24,26,28), whereas a diffuse Tau1 labeling is observed in murine neuronal cells (27).…”