Evidence for an imbalance between tau O-GlcNAcylation and phosphorylation in the hippocampus of a mouse model of Alzheimer’s disease

Gatta, Eleonora; Lefebvre, Tony; Gaetani, Silvana; Santos, Marc Dos; Marrocco, Jordan; Mir, Anne Marie; Cassano, Tommaso; Maccari, Stefania; Nicoletti, Ferdinando; Mairesse, Jérôme

doi:10.1016/j.phrs.2016.01.006

Cited by 41 publications

(32 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, O-GlcNAc signaling has been characterized in numerous pathologies outside of the nervous system [49-52]. To date, O-GlcNAc has been limited to studies in the nervous system only with respects to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, seizures, appetite, and synaptic plasticity [14-20, 53, 54]…”

Section: Discussionmentioning

confidence: 99%

“…By inhibiting OGA, Thiamet-G can thus be used to increase global levels of O-GlcNAcylation within eukaryotic cells [13]. Recently, several studies have focused on O-GlcNAcylation in neurological disorders such as Alzheimer’s, Parkinson’s, Huntington’s, Schizophrenia, and other nervous system processes such as appetite, LTD, hyper-excitability and protein structure [14-23]. However, the role of OGT/OGA cycling and protein O-GlcNAcylation in the epileptic hippocampus and the question of whether O-GlcNAc pathways could be targeted for treatment of TLE remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GLCNAC Homeostasis that can be Reversed to Dampen Epileptiform Activity

Sánchez

Parrish

Rich

et al. 2018

Preprint

View full text Add to dashboard Cite

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein 24 composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-β-N-25 acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that integrate 26 energy supply with demand. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) 27 mediate the addition and removal, respectively, of the O-GlcNAc modification. The goal of this 28 study was to determine whether changes in OGT/OGA cycling and disruptions in protein O-29 GlcNAcylation occur in the epileptic hippocampus. We observed reduced global and protein specific 30 O-GlcNAcylation and OGT expression in the kainate rat model of TLE and in human TLE 31 hippocampal tissue. Inhibiting OGA with Thiamet-G elevated protein O-GlcNAcylation, and 32 decreased both seizure duration and epileptic spike events, suggesting that OGA may be a 33 therapeutic target for seizure control. These findings suggest that loss of O-GlcNAc homeostasis in 34 the kainate model and in human TLE can be reversed via targeting of O-GlcNAc related pathways. 35

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GLCNAC Homeostasis that can be Reversed to Dampen Epileptiform Activity

Sánchez

Parrish

Rich

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Dysregulation of O-GlcNAcylation is also associated with neurodegenerative disorders including Alzheimer's disease as previously documented (9). While a reciprocal relationship between O-GlcNAcylation and phosphorylation on Tau protein has been reported (10,11), molecular details of this interaction remain largely unknown. Bourré et al used NMR spectroscopy approach to map O-GlcNAc sites on the longest isoform of Tau and to gain insight into the crosstalk between O-GlcNAcylation and phosphorylation.…”

mentioning

confidence: 90%

Editorial: O-GlcNAcylation: Expanding the Frontiers

Issad

Lefebvre

2019

Front. Endocrinol.

Self Cite

View full text Add to dashboard Cite

“…An in vivo study of triple Tg AD mice revealed that there was a critical imbalance in phosphorylation and O‐GlcNAcylation. Tau was hyperphosphorylated at Ser396 and Thr205 in the hippocampus and the O‐GlcNAcylation level dropped significantly in advanced stages (12 months old) of the AD mouse model . A study of the AD brain samples showed that O‐GlcNAcylation of tau was significantly reduced and negatively correlated with the phosphorylation level.…”

Section: Glycosylationmentioning

confidence: 99%

Role of Post‐translational Modifications in Alzheimer's Disease

2020

View full text Add to dashboard Cite

The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug‐discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post‐translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in‐depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease‐relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug‐discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.

show abstract

Evidence for an imbalance between tau O-GlcNAcylation and phosphorylation in the hippocampus of a mouse model of Alzheimer’s disease

Cited by 41 publications

References 53 publications

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GLCNAC Homeostasis that can be Reversed to Dampen Epileptiform Activity

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GLCNAC Homeostasis that can be Reversed to Dampen Epileptiform Activity

Editorial: O-GlcNAcylation: Expanding the Frontiers

Role of Post‐translational Modifications in Alzheimer's Disease

Contact Info

Product

Resources

About