The O-GlcNAc Modification of CDK5 Involved in Neuronal Apoptosis Following In Vitro Intracerebral Hemorrhage

Ning, Xiaojin; Tao, Tao; Shen, Jianhong; Ji, Yuteng; Xie, Lili; Wang, Hongmei; Liu, Ning; Xu, Xide; Sun, Chi; Zhang, Dongmei; Shen, Aiguo; Ke, Kaifu

doi:10.1007/s10571-016-0391-y

Cited by 20 publications

(13 citation statements)

References 35 publications

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“…Higher O-GlcNAc levels have been shown to be associated with cellular apoptosis in different cell and tissue types including heart muscle, pancreatic beta cells and neurons (Liu et al, 2000 , 2004 ; Dassanayaka and Jones, 2014 ; Zhu et al, 2015 ; Ning et al, 2017 ). We therefore reasoned that the reduction in the numbers of KI-67 positive cells observed in TMG treated samples during cortical differentiation (Figures 4D,E ) could be a result of increased cell death.…”

Section: Resultsmentioning

confidence: 99%

“…At the cellular level, increased O-GlcNAc levels induce neuronal apoptosis (Shi et al, 2015 ). Among the various other mechanisms, dynamic interplay of post-translational O-GlcNAcylation and phosphorylation of specific proteins is known to be responsible for cellular apoptosis in the brain (Liu et al, 2004 ; Zhu et al, 2015 ; Ning et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

Parween

Varghese

Ardah

et al. 2017

Front. Cell. Neurosci.

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The nutrient responsive O-GlcNAcylation is a dynamic post-translational protein modification found on several nucleocytoplasmic proteins. Previous studies have suggested that hyperglycemia induces the levels of total O-GlcNAcylation inside the cells. Hyperglycemia mediated increase in protein O-GlcNAcylation has been shown to be responsible for various pathologies including insulin resistance and Alzheimer's disease. Since maternal hyperglycemia during pregnancy is associated with adverse neurodevelopmental outcomes in the offspring, it is intriguing to identify the effect of increased protein O-GlcNAcylation on embryonic neurogenesis. Herein using human embryonic stem cells (hESCs) as model, we show that increased levels of total O-GlcNAc is associated with decreased neural progenitor proliferation and premature differentiation of cortical neurons, reduced AKT phosphorylation, increased apoptosis and defects in the expression of various regulators of embryonic corticogenesis. As defects in proliferation and differentiation during neurodevelopment are common features of various neurodevelopmental disorders, increased O-GlcNAcylation could be one mechanism responsible for defective neurodevelopmental outcomes in metabolically compromised pregnancies such as diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

Parween

Varghese

Ardah

et al. 2017

Front. Cell. Neurosci.

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“…CDK5 represses neuronal cell-cycle advancement (40) and is an important upstream regulator of oxidative stress through phosphorylation of peroxiredoxin I/II and p53 (39). Interestingly, a recent paper suggests that blocking O-GlcNAcylation of CDK5 can lead to neuronal apoptosis by enhancing its association with the p53 pathway (41). Several other studies have implicated aberrant cell-cycle advancement in ADassociated neurodegeneration through deregulation of CDK5 levels and activity (40,42).…”

Section: Discussionmentioning

confidence: 99%

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Wang

Jensen

Rexach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

162

137

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O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer’s disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.

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“…There are numerous reports of O-GlcNAcylation altering mitochondrial function linked to apoptosis(Shin et al, 2011; Palaniappan et al, 2013; Bond and Hanover, 2015; Zhu et al, 2015a; Wani et al, 2016a; van der Harg et al, 2017). A link between apoptosis and neurodegenerative disease has been made in some studies (Liu et al, 2004b; Zhu et al, 2015a; Chen et al, 2017; Ning et al, 2017). Knockout of Ogt in excitatory neurons led to neurodegeneration with some indications that apoptosis-related genes might be altered (Wang et al, 2016), whereas another study showed no effect on apoptosis or neuron viability (Lagerlöf et al, 2016).…”

Section: O-glcnac: a Central Role In Cellular Regulation Of Neuronmentioning

confidence: 99%

“…In response to a mitogenic signal, protein O-GlcNAcylation increases as does localization of O-GlcNAc modified proteins to the nucleus (Kearse and Hart, 1991a). Functional studies of O-GlcNAc modified proteins such as p53 (Yang et al, 2006), p27 (Qiu et al, 2017), cyclin D1 (Olivier-Van Stichelen et al, 2012), CDK5 (Ning et al, 2017), c-myc (Chou et al, 1995), beta-catenin (Olivier-Van Stichelen et al, 2014b), NF-kB (Yang et al, 2008a; Kawauchi et al, 2009; Ramakrishnan et al, 2013), FoxM1 (Caldwell et al, 2010), HCF-1 (Capotosti et al, 2011), and Erk1/2 (Jiang et al, 2016) have been critical for furthering the understanding of O-GlcNAc in cell cycle progression. Key AD players are known to be O-GlcNAc modified including APP and tau, which have also been implicated in cell cycle regulation.…”

Section: O-glcnac: a Central Role In Cellular Regulation Of Neuronmentioning

confidence: 99%

Nutrient‐driven O‐GlcNAc in proteostasis and neurodegeneration

Akan

Stichelen

Bond

et al. 2017

Journal of Neurochemistry

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Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-GlcNAc transferase- and O-GlcNAcase-knockout alleles have helped define the role O-GlcNAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-GlcNAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-GlcNAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-GlcNAc cycling. Like the quality control system in the endoplasmic reticulum which uses a 'mannose timer' to monitor protein folding, we propose that cytoplasmic proteostasis relies on an 'O-GlcNAc timer' to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-GlcNAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-GlcNAc in the physiology of the brain and its susceptibility to neurodegenerative injury.

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The O-GlcNAc Modification of CDK5 Involved in Neuronal Apoptosis Following In Vitro Intracerebral Hemorrhage

Cited by 20 publications

References 35 publications

Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

Loss of O -GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration

Nutrient‐driven O‐GlcNAc in proteostasis and neurodegeneration

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