Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

Abstract : Tau is an intrinsically disordered microtubule associated protein that is implicated in several neurodegenerative disorders called Tau opathies. In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the importance of this irreversible PHF formation in neurodegenerative disease, Tau aggregation has been extensively studied. Several different factors, such as mutations or post translational modifications, have been shown to influence the formation of late stage non-reversible Tau aggregates. It was recently shown that zinc ions accelerated heparin induced oligomerization of Tau constructs. Indeed, in vitro studies of PHFs have usually been performed in the presence of additional co-factors, such as heparin, in order to accelerate their formation. Using turbidimetry, we investigated the impact of zinc ions on Tau in the absence of heparin and found that zinc is able to induce a temperature dependent reversible oligomerization of Tau. The obtained oligomers were not amyloid like, and dissociated instantly following zinc chelation or a temperature decrease. Finally, a combination of isothermal titration calorimetry and dynamic light scattering experiments showed zinc binding to a high affinity binding site and three low affinity sites on Tau, accompanied by a change in Tau folding. Altogether, our findings stress the importance of zinc in Tau oligomerization. This newly identified Zn-induced oligomerization mechanism may be a part of a pathway different of and concurrent to Tau aggregation cascade leading to PHF formation.
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Andrei Roman, François Devred, Deborah Byrne, Romain La Rocca, Natalia Ninkina, et al.. Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau. Journal of Molecular Biology, Elsevier, 2018, ⟨10.1016/j.jmb.2018.12.008⟩. ⟨hal-01981683v2⟩

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