Phosphorylation and Dephosphorylation of Tau Protein During Synthetic Torpor

Abstract

Tau protein is of primary importance for many physiological processes in neurons, where it affects the dynamics of the microtubule system. When hyperphosphorylated (PP-Tau), Tau monomers detach from microtubules and tend to aggregate firstly in oligomers, and then in neurofibrillary tangles, as it occurs in a group of neurodegenerative disorders named thauopathies. A hypothermia-related accumulation of PP-Tau, which is quickly reversed after the return to normothermia, has been shown to occur in the brain of hibernators during torpor. Since, recently, in our lab, a hypothermic torpor-like condition (synthetic torpor, ST) was pharmacologically induced in the rat, a non-hibernator, the aim of the present work was to assess whether ST can lead to a reversible PP-Tau accumulation in the rat brain. PP-Tau was immunohistochemically assessed by staining for AT8 (phosphorylated Tau) and Tau-1 (non-phosphorylated Tau) in 19 brain structures, which were chosen mostly due to their involvement in the regulation of autonomic and cognitive functions in relation to behavioral states. During ST, AT8 staining was strongly expressed throughout the brain, while Tau-1 staining was reduced compared to control conditions. During the following recovery period, AT8 staining progressively reduced close to zero after 6 h from ST. However, Tau-1 staining remained low even after 38 h from ST. Thus, overall, these results show that ST induced an accumulation of PP-Tau that was, apparently, only partially reversed to normal during the recovery period. While the accumulation of PP-Tau may only depend on the physicochemical characteristics of the enzymes regulating Tau phosphorylation, the reverse process of dephosphorylation should be actively regulated, also in non-hibernators. In conclusion, in this work a reversible and widespread PP-Tau accumulation has been induced through a procedure that leads a non-hibernator to a degree of reversible hypothermia, which is comparable to that observed in hibernators. Therefore, the physiological mechanism involved in this process can sustain an adaptive neuronal response to extreme conditions, which may however lead to neurodegeneration when particular intensities and durations are exceeded.

The Torpid State: Recent Advances in Metabolic Adaptations and Protective Mechanisms†

“…Therefore, exploring these outstanding mechanisms occurring naturally in heterothermic models constitutes a unique opportunity to develop efficient responses, tools and treatments to address major environmental and health concerns. Specifically, the study of these mechanisms have potential for a better understanding of (i) protective responses against metabolic disorders such as obesity or sarcopenia ( Cotton, 2016 ), (ii) the homeostasis of neuronal functions, e.g., the maintenance of hyper-phosphorylation of Tau proteins involved in resistance to neuro-degenerative diseases ( Härtig et al, 2007 ; Luppi et al, 2019 ), and (iii) the underlying mechanisms for a state of hypothermia in humans, also called “synthetic torpor,” for therapeutic goals ( Cerri, 2017 ) or space exploration ( Choukèr et al, 2019 ). In the context of the latter, the study of protective mechanisms for the torpid brain is of particular interest as well as the implications for the gaseous molecule H 2 S involved in the potential control and maintenance of metabolic depression and protective mechanisms in the torpid state.…”

Reversible Tau Phosphorylation Induced by Synthetic Torpor in the Spinal Cord of the Rat

“…The animals used for the present work were the same as those used in the experiment described in Luppi et al ( 2019 ). In contrast, however, the present work is focused on the SpCo, a division of the nervous system that was not considered in our previous analysis.…”

“…To induce ST, we used a consolidated protocol (Cerri et al, 2013 ; Luppi et al, 2019 ; Tinganelli et al, 2019 ). Briefly, a microinjecting cannula was inserted into the implanted guide cannula.…”

“…Since in Luppi et al ( 2019 ) the study focused on the brain, a dedicated study on the SpCo appears of particular interest concerning two main objectives: (i) to integrate and complete the knowledge of phosphorylation/dephosphorylation processes of Tau protein in the central nervous system during ST; (ii) to better define the possible parallelism of these processes with those occurring in tauopathies. Therefore, we sought to assess the expression of PP-Tau in the SpCo of rats, during both the induction of ST and the following recovery period.…”

Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology

“…However, a group reported that in Arctic ground squirrel, some sites were dephosphorylated in arousal animals while others remained phosphorylated, indicating a reversible phosphorylation at selective sites ( 84 ). Similarly, tau hyperphosphorylation was shown to be partially reversed in a model inducing a hypothermic torpor-like state ( 129 ). Although hypothermia could contribute to tau hyperphosphorylation during hibernation, it was clearly demonstrated that it was not sufficient and that tau phosphorylation is regulated by other mechanisms that remain to be identified.…”