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Data from: O-GlcNAc modification differentially regulates microtubule binding and pathological conformations of tau isoforms in vitro

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Mar 20, 2025 version files 3.06 GB

Abstract

Tau proteins undergo several post-translational modifications (PTMs) in physiological and disease conditions. In Alzheimer’s disease, O-linked β-d-N-acetylglucosamine (O-GlcNAcylation) modification of serine/threonine (S/T) residues in tau is reduced. In mouse models of tauopathy, O-GlcNAcase inhibitors lead to increased O-GlcNAcylation and decreased filamentous aggregates of tau. However, various non-filamentous tau conformations, linked to toxicity and neurodegeneration in tauopathies, involve processes like oligomerization, misfolding, and greater exposure of the phosphatase-activating domain in the amino-terminus of tau. Additionally, it is becoming clearer that PTMs may differently regulate tau pathobiology in an isoform-dependent manner. Therefore, it is crucial to investigate the effects of O-GlcNAcylation on non-filamentous conformations of both the 4-repeat (4R, e.g. hT40) and 3-repeat (3R, e.g. hT39) tau isoforms. In this study, we assessed how O-GlcNAcylation impacts pathological tau conformations of the longest 4R and 3R tau isoforms (hT40 and hT39, respectively) using recombinant proteins. Mass spectrometry showed that tau is modified with O-GlcNAc at multiple S/T residues, primarily in the proline-rich domain and the C-terminal region. O-GlcNAcylation of hT40 and hT39 does not affect microtubule polymerization but has opposite effects on hT40 (increases) and hT39 (decreases) binding to pre-formed microtubules. Although O-GlcNAcylation interferes with forming filamentous hT40 aggregates, it does not alter the formation of pathological non-filamentous tau conformations. On the other hand, O-GlcNAcylation increases the formation of pathological non-filamentous hT39 conformations. These findings suggest that O-GlcNAcylation differentially modulates microtubule binding and the adoption of pathological tau conformations in the longest 4R and 3R tau isoforms.