Abstract
Tau hyperphosphorylation can be considered as one of the hallmarks of Alzheimer's disease and other tauophaties. Besides its well-known role as a microtubule associated protein, Tau displays a key function as a protector of genomic integrity in stress situations. Phosphorylation has been proven to regulate multiple processes including nuclear translocation of Tau. In this contribution, we are addressing the physicochemical nature of DNA-Tau interaction including the plausible influence of phosphorylation. By means of surface plasmon resonance (SPR) we measured the equilibrium constant and the free energy, enthalpy and entropy changes associated to the Tau-DNA complex formation. Our results show that unphosphorylated Tau binding to DNA is reversible. This fact is in agreement with the protective role attributed to nuclear Tau, which stops binding to DNA once the insult is over. According to our thermodynamic data, oscillations in the concentration of dephosphorylated Tau available to DNA must be the variable determining the extent of Tau binding and DNA protection. In addition, thermodynamics of the interaction suggest that hydrophobicity must represent an important contribution to the stability of the Tau-DNA complex. SPR results together with those from Tau expression in HEK cells show that phosphorylation induces changes in Tau protein which prevent it from binding to DNA. The phosphorylation-dependent regulation of DNA binding is analogous to the Tau-microtubules binding inhibition induced by phosphorylation. Our results suggest that hydrophobicity may control Tau location and DNA interaction and that impairment of this Tau-DNA interaction, due to Tau hyperphosphorylation, could contribute to Alzheimer's pathogenesis.
Highlights
The results we present here prove that, to the Taumicrotubules interaction, Tau-DNA interaction is dependent on the phosphorylation state of the protein, as shown by surface plasmon resonance and Tau expression in human embryonic kidney 293 (HEK) cells
Tau is present inside the nuclei, it seems to represent a minor proportion of total Tau
In these cases where nuclear membrane disappears, certain proportion of labeled Tau protein share the same regions occupied by chromosomes, suggesting that a fraction of Tau colocalizes with DNA at some stages of cell division
Summary
Together with the extracellular senile plaques, the intracellular tangles composed mainly of Tau protein, forming the paired helical filaments (PHFs), are the second type of aberrant proteinaceous aggregates found associated to Alzheimer’s disease [12,13,14,15]. Tau is a highly soluble protein devoid of any well-defined secondary or tertiary structure, as many other proteins prone to aggregation and fibrillization involved in neurodegenerative diseases. A survey of Tau literature leads one to conclude that aggregation and hyperphosphorylation must have a particular role in the neurodegenerative processes [16,17]. A precise knowledge of those particular molecular events involving Tau protein in Alzheimer’s disease yet remains elusive
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