Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 426, Issue 8, Pages 1736-1752Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2014.01.004
Keywords
tauopathy; Alzheimer's disease; glycosylation; paired helical filaments; NMR spectroscopy
Categories
Funding
- Canadian Institutes of Health Research [MOP 275394]
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Alzheimer Society of Canada
- NSERC
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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-GIcNAc). Previously, increased O-GIcNAcylation of tau has been shown to block the accumulation of tau aggregates within a tauopathy mouse model. Here we show that O-GIcNAc modification of full-length human tau impairs the rate and extent of its heparin-induced aggregation without perturbing its activity toward microtubule polymerization. O-GIcNAcylation, however, does not impact the global-fold of tau as measured by a Forster resonance energy transfer assay. Similarly, nuclear magnetic resonance studies demonstrated that O-GIcNAcylation 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 GIcNAc-acceptor Ser400. These data indicate that the inhibitory effects of O-GIcNAc 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-GIcNAc pathway for potential Alzheimer's disease therapeutics. (C) 2014 Elsevier Ltd. All rights reserved.
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