O-GlcNAc Modification of tau Directly Inhibits Its Aggregation without Perturbing the Conformational Properties of tau Monomers

Abstract

The aggregation of the microtubule-associated protein tau into paired helical filaments to form neurofibrillary tangles constitutes one of the pathological hallmarks of Alzheimer's disease. Tau is post-translationally modified by the addition of N-acetyl-D-glucosamine O-linked to several serine and threonine residues (O-GlcNAc). Previously, increased O-GlcNAcylation of tau has been shown to block the accumulation of tau aggregates within a tauopathy mouse model. Here we show that O-GlcNAc modification of full-length human tau impairs the rate and extent of its heparin-induced aggregation without perturbing its activity toward microtubule polymerization. O-GlcNAcylation, however, does not impact the "global-fold" of tau as measured by a Förster resonance energy transfer assay. Similarly, nuclear magnetic resonance studies demonstrated that O-GlcNAcylation only minimally perturbs the local structural and dynamic features of a tau fragment (residues 353-408) spanning the last microtubule binding repeat to the major GlcNAc-acceptor Ser400. These data indicate that the inhibitory effects of O-GlcNAc on tau aggregation may result from enhanced monomer solubility or the destabilization of fibrils or soluble aggregates, rather than by altering the conformational properties of the monomeric protein. This work further underscores the potential of targeting the O-GlcNAc pathway for potential Alzheimer's disease therapeutics.

Tau: From research to clinical development

“…Studies in bigenic MAPT/APP mutant mice showed that inhibition of OGA prevented cognitive decline and amyloid plaque formation [51] and in JNPL3, tauopathy mice acted to block the formation of hyperphosphorylated tau, the development of tau aggregates, and neurodegeneration [52]. Various protective mechanisms are possible; however, it is interesting to note that O-GlcNAcylation of tau was recently shown to attenuate tau aggregation in vitro [53]. Inhibiting acetylation of tau has also been proposed as a therapeutic strategy.…”

The Emerging Link between O-GlcNAc and Alzheimer Disease

“…Surprisingly, however, sustained OGA inhibition over a period of months did not lead to a reduction in phosphorylation of soluble tau (78), causing the authors to speculate that O-GlcNAc may itself hinder tau aggregation independent of phosphorylation. Analysis of various aggregation-prone tau fragments (78) and, more recently, full-length tau (84) showed that O-GlcNAc at Ser-400 hinders aggregation of tau in vitro without affecting the conformation of tau.…”

Many Light Touches Convey the Message

“…Similarly, O-GlcNAc modification may increase ensemble dynamics and thereby suppress precipitation of aggregation-prone proteins. Interestingly, pharmacological intervention that increases O-GlcNAc is reported to inhibit tau protein aggregation in vitro [47] and to prevent amyloid plaque formation in a mouse model of Alzheimer's disease [48]. O-GlcNAc emerged in metazoans and O-GlcNAc-modified Nup98 gel lacks the amyloid-like b structures found in the rigid regions of the S. cerevisiae Nups that are required for hydrogel formation.…”