Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies

Domenico, Fabio Di; Lanzillotta, Chiara; Tramutola, Antonella

doi:10.1080/14737175.2019.1540932

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…Recent evidence has demonstrated that O-GlcNAc perturbation affects the splicing of the highly conserved detained introns in OGT and OGA in order to control mRNA abundance, altering OGT and OGA protein levels to buffer changes in O-GlcNAc [100,101]. On the other hand, an uncoupling of OGT/OGA levels and altered O-GlcNAcylation has been reported in different diseases, suggesting a role in pathology progression [27,40,42,97,102]. In Ts2 mice, the relevant reduction in protein O-GlcNAcylation was concomitant with a significant increase of both OGA transcript and protein levels, hinting at a lack of compensation for O-GlcNAc imbalance.…”

Section: Discussionmentioning

confidence: 99%

“…The accepted hypothesis is that the general decrease of protein O-GlcNAcylation associated with the specific reduction of APP and tau GlcNAc levels may promote Aβ plaque formation and tau aggregation in the brain, thus contributing to cognitive decline [37,[42][43][44][45]. Noteworthy, several studies reported the increase of O-GlcNAc levels in the brain of AD subjects suggesting a more complex crosstalk between O-GlcNAcylation and neurodegenerative processes [42,46,47].…”

Section: Introductionmentioning

confidence: 99%

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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

et al. 2021

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Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers. Down syndrome (DS) individuals are characterized by the early development of AD by the age of 60 and, although the two conditions present the same pathological hallmarks and share the alteration of many molecular mechanisms driving brain degeneration, no evidence has been sought on the implication of O-GlcNAcylation in DS pathology. Our study aimed to unravel for the first time the role of protein O-GlcNacylation in DS brain alterations positing the attention of potential trisomy-related mechanisms triggering the aberrant regulation of OGT/OGA cycle. We demonstrate the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

et al. 2021

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“…It has been proposed that O-linked Tau glycosylation reduces Tau aggregation through the prevention of its phosphorylation on the same residues, 212,[219][220][221] pointing to the importance of the temporal sequence of Tau modifications. The deglycosylation of already hyperphosphorylated Tau derived from the cytosolic fraction of AD patients' brains, failed to induce its fibrillization.…”

Section: Determinants Of Tau Aggregationmentioning

confidence: 99%

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Limorenko

Lashuel

2022

Chem. Soc. Rev.

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“…The addition of β-linked Nacetylglucosamine (O-GlcNAcylation) is the non-canonical form is glycosylation, and the levels are strictly regulated by O-GlcNAc transferase and neutral β-hexosaminidase known as O-GlcNAcase (OGA). Since serine and threonine residues undergo O-GlcNAcylation (Arnold et al, 1996), there is a competition between O-GlcNAcylation and phosphorylation (Liu et al, 2004;Hart et al, 2007;Di Domenico et al, 2019). In P301L tau transgenic mice (JNPL3), an OGA inhibitor was found to increase tau O-GlcNAcylation, thereby inhibiting the formation of tau aggregates and neuronal loss (Yuzwa et al, 2012).…”

Section: O-glcnacylationmentioning

confidence: 99%

New Insights Into Drug Discovery Targeting Tau Protein

Soeda

Takashima

2020

Front. Mol. Neurosci.

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Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies

Cited by 15 publications

References 26 publications

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

New Insights Into Drug Discovery Targeting Tau Protein

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