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Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Phosphorylation
Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Research
Dr. Andrew D. R. Brown is a neuroscientist at Cardiff University, School of Biosciences, whose research centers on the mechanistic relationship between protein O-GlcNAcylation and phosphorylation on tau protein, and how their imbalance contributes to neurodegeneration in Alzheimer's disease and related tauopathies.
Background
| Attribute | Details |
|-----------|--------|
| Current Position | Senior Research Fellow |
| Institution | Cardiff University, School of Biosciences |
| Location | Cardiff, Wales, UK |
| Research Focus | Tau O-GlcNAcylation, tau phosphorylation, post-translational modification balance, neurodegeneration |
Education and Training:
- PhD in Biochemistry: University of Cambridge — thesis on protein glycosylation in the CNS
- Postdoctoral Training: University of Edinburgh, then Cardiff University — focused on tau biology and post-translational modifications
Research Contributions
The Yin-Yang Hypothesis of Tau PTM Crosstalk
Dr. Brown's research centers on the concept that O-GlcNAcylation and phosphorylation on tau protein exist in a dynamic "yin-yang" relationship, where they compete for the same or adjacent serine/threonine residues and mutually regulate each other's functional consequences[@smet2011][@wani2016].
Dr. Andrew D. R. Brown — O-GlcNAcylation and Tau Research
Dr. Andrew D. R. Brown is a neuroscientist at Cardiff University, School of Biosciences, whose research centers on the mechanistic relationship between protein O-GlcNAcylation and phosphorylation on tau protein, and how their imbalance contributes to neurodegeneration in Alzheimer's disease and related tauopathies.
Background
| Attribute | Details |
|-----------|--------|
| Current Position | Senior Research Fellow |
| Institution | Cardiff University, School of Biosciences |
| Location | Cardiff, Wales, UK |
| Research Focus | Tau O-GlcNAcylation, tau phosphorylation, post-translational modification balance, neurodegeneration |
Education and Training:
- PhD in Biochemistry: University of Cambridge — thesis on protein glycosylation in the CNS
- Postdoctoral Training: University of Edinburgh, then Cardiff University — focused on tau biology and post-translational modifications
Research Contributions
The Yin-Yang Hypothesis of Tau PTM Crosstalk
Dr. Brown's research centers on the concept that O-GlcNAcylation and phosphorylation on tau protein exist in a dynamic "yin-yang" relationship, where they compete for the same or adjacent serine/threonine residues and mutually regulate each other's functional consequences[@smet2011][@wani2016].
Foundational framework: O-GlcNAcylation and phosphorylation compete for overlapping sites on tau. The same residues can be modified by either modification depending on cellular context. While phosphorylation promotes tau aggregation and microtubule destabilization, O-GlcNAcylation stabilizes tau in a less pathological conformation[@smet2011].
Site-specific mapping: Mass spectrometry studies have mapped O-GlcNAcylation sites on tau protein, identifying residues in the microtubule-binding repeat domain that are also targets for disease-relevant phosphorylation:
- Threonine 212: A major O-GlcNAcylation site that, when modified, prevents phosphorylation at adjacent sites and reduces tau's aggregation propensity[@smet2011]
- Serine 396/404: O-GlcNAcylation at these sites reduces downstream phosphorylation events that promote paired helical filament formation
- Multiple sites in the repeat domain: The 4R-tau-specific inclusions in PSP and CBD show differential O-GlcNAcylation patterns compared to 3R-tau pathologies in AD
O-GlcNAcylation as a Therapeutic Target
Dr. Brown's work supports the hypothesis that increasing O-GlcNAcylation through OGA inhibition can protect against tau pathology[@wang2018][@pan2021].
Evidence for neuroprotection: Experimental work has demonstrated that:
- Pharmacological OGA inhibition elevates tau O-GlcNAcylation and reduces tau phosphorylation at key pathological sites[@yu2012]
- OGA inhibitor treatment reduces tau aggregation in cellular models of tauopathy[@wang2018]
- In mouse models of tauopathy, OGA inhibitors reduce phosphorylated tau burden and improve behavioral outcomes[@pan2021][@rostgaard2023]
- The protective effect involves both direct competition at modification sites and indirect effects on kinase/phosphatase activity[@lu2020]
- Decreased O-GlcNAc transferase (OGT) expression and activity in neurons
- Increased O-GlcNAcase (OGA) expression and activity
- Reduced UDP-GlcNAc availability due to altered glucose metabolism
- Accumulation of oxidative stress that impairs OGT function[@katai2016]
Therapeutic Implications
The O-GlcNAcylation deficit creates a therapeutic window where OGA inhibitors can restore tau protection[@pratt2023].
Key therapeutic approaches:
Recent Research
2024-2025 Updates
- Xia L, et al. "Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice" — Demonstrated that DHA promotes tau O-GlcNAcylation and improves cognition in tauopathy models (Aging Cell, 2024)[@xia2024]
- Rostgaard N, et al. "Increasing O-GlcNAcylation Attenuates tau Hyperphosphorylation and Behavioral Impairment in rTg4510 Tauopathy Mice" — Showed that increasing O-GlcNAcylation reduces tau pathology and behavioral deficits (Molecular Neurobiology, 2023)[@rostgaard2023]
- Pratt MR, et al. "Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases" — Comprehensive review of O-GlcNAcbiology in neurodegeneration and therapeutic opportunities (ACS Chemical Biology, 2023)[@pratt2023]
2022-2023 Updates
- Pan DM, et al. "Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice" — Novel OGA inhibitor with improved brain penetration (ACS Chemical Neuroscience, 2021)[@pan2021]
- Lu S, et al. "SIRT1 regulates O-GlcNAcylation of tau through OGT" — Identified SIRT1 as a regulator of tau O-GlcNAcylation (Aging Cell, 2020)[@lu2020]
Key Publications
See Also
- [O-GlcNAcylation Pathway](/mechanisms/protein-o-glcna-cylation-pathway)
- [Tau Phosphorylation Pathway](/mechanisms/tau-phosphorylation-pathway)
- [OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-psp)
- [Tauopathies](/diseases/tauopathies)
- [Cardiff University](/institutions/cardiff-university)
References
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