A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
Abstract
Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K(i) = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.
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O-GlcNAcylation negatively regulates tau phosphorylation.
“O-GlcNAcylation negatively regulates tau phosphorylation, as Ser and Thr targets for O-GlcNAcylation and phosphorylation overlap to some extent.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [188]
Downregulation of O-GlcNAc transferase leads to reduced O-GlcNAcylation and increased tau phosphorylation.
“Downregulation of O-GlcNAc transferase leads to reduced O-GlcNAcylation and increased tau phosphorylation”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [188]
Inhibition of O-GlcNAcase reduces tau phosphorylation.
“whereas inhibition of O-GlcNAcase reduces tau phosphorylation [187, 188].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [188]
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- Authors
- Yuzwa, S. A., Macauley, M. S., Heinonen, J. E., Shan, X., Dennis, R. J., He, Y., Whitworth, G. E., Stubbs, K. A., McEachern, E. J., Davies, G. J., & Vocadlo, D. J.
- Affiliations
- Simon Fraser University (CA)
- University of York (GB)
- Corresponding author
- Vocadlo, David J
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2008-06-29
- Volume
- 4
- Issue
- 8
- Pages
- 483-490
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2060744329
- Cited by
- 717
- References
- 48
- Citations by year
- 2026: 27 · 2025: 43 · 2024: 47 · 2023: 39 · 2022: 39 · 2021: 51 · 2020: 43 · 2019: 37 · 2018: 42 · 2017: 49 · 2016: 39 · 2015: 39 · 2014: 40 · 2013: 41 · 2012: 42
- FWCI
- 22.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- Simon Fraser University
- Canadian Institutes of Health Research
- Biotechnology and Biological Sciences Research Council (BB/F007124/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Keywords
- O-GlcNAcase inhibitors, Thiamet G, tau hyperphosphorylation, O-GlcNAcylation, Alzheimer's disease, tauopathy, PC12 cells, rat cortex, hippocampus, rational drug design
- MeSH terms
- Animals, beta-N-Acetylhexosaminidases, Brain Chemistry, Cerebral Cortex, Enzyme Inhibitors, Hippocampus, Humans, Phosphorylation, tau Proteins, Tauopathies, Rats
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