Yuzwa, S. A. et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nature Chem. Biol. 4, 483-490

Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.
Nature Chemical Biology (Impact Factor: 13). 09/2008; 4(8):483-90. DOI: 10.1038/nchembio.96
Source: PubMed


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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    • "Different from other O-GlcNAcylation modulating drugs, such as O-(2-Acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenyl carbamate (PUBNAc) and Streptozotocin (STZ), NButGT was specific to O-GlcNAcase and showed the lack of cellular toxicity nor insulin resistance (122). Additionally, O-GlcNAcase inhibitor was reported to reduce the tau phosphorylation and improve long-term potentiation (LTP) as well, which are possibly beneficial in AD (123, 124). O-GlcNAcase inhibitor seems to be effective not only in Aβ generation but also in memory impairment and taupathies, which is needed to be further verified in future clinical studies. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.
    Full-text · Article · Jul 2014 · Journal of Korean Medical Science
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    • "Due to the importance of O-GlcNAcase for human health, the research of specific inhibitors based on the knowledge of the structure and catalytic mechanism is quickly progressing (reviewed in [23]). Among all compounds designed and tested as O-GlcNAcase inhibitors, thiamet-G is the lead molecule , as it has been shown to slow down neurodegeneration and stabilize protein tau against aggregation by hindering the action of O-GlcNAcase in a mouse model, which makes thiamet-G a potential Alzheimer's therapeutic [24] [25]. Here we report on the first non-mammalian eukaryotic b-N-acetylglucosaminidase from Penicillium chrysogenum, which was expressed in a yeast expression system, purified and characterized. "
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    ABSTRACT: β-N-Acetylglucosaminidases from the family 84 of glycoside hydrolases form a small group of glycosidases in eukaryotes responsible for the modification of nuclear and cytosolic proteins with O-GlcNAc, thus they are involved in a number of important cell processes. Here, the first fungal β-N-acetylglucosaminidase from Penicillium chrysogenum was expressed in Pichia pastoris and secreted into the media, purified and characterized. Moreover, homology modeling and substrate and inhibitor docking were performed to obtain structural information on this new member of the GH84 family. Surprisingly, we found that this fungal β-N-acetylglucosaminidase with its sequence and structure perfectly fitting to the GH84 family displays biochemical properties rather resembling the β-N-acetylhexosaminidases from the family 20 of glycoside hydrolases. This work helped to increase the knowledge on the scarcely studied glycosidase family and revealed a new type of eukaryotic β-N-acetylglucosaminidase.
    Full-text · Article · Jan 2014 · Protein Expression and Purification
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    • "Antibody ab3925 was tested because it was specifically raised against the O-GlcNAc-ylated S400 epitope in protein tau [10,11]. The antibody ab3925 reacted more strongly with samples I, but again not with protein tau expressed in bacteria, although some high Mr bacterial proteins cross-reacted (samples II, middle panel, Figure 5A). "
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    ABSTRACT: The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.
    Full-text · Article · Dec 2013 · PLoS ONE
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