O-GlcNAc cycling in the developing, adult and geriatric brain

Lagerlöf, Olof

doi:10.1007/s10863-018-9760-1

Cited by 28 publications

(21 citation statements)

References 239 publications

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“…Although most glucose is used to generate ATP and lactate, during glucose metabolism, some of the available glucose is used for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), which serves as a donor molecule for O-GlcNAcylation. O-GlcNAcylation is a dynamic post-translational modification (PTM) that fine-tunes multiple processes governing fundamental cellular processes, such as signal transduction, transcription, translation, and proteasomal degradation ( Hart et al, 2007 ; Yang and Qian, 2017 ; Lagerlof, 2018 ). The enzyme O-GlcNAc transferase (OGT) catalyzes the covalent attachment of N-acetyl-D-glucosamine to serine or threonine residues of proteins, whereas β-N-acetylhexosaminidase (also known as O-GlcNAcase [OGA]) catalyzes its removal.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Astrocytic O-GlcNAc Transferase-Related Proteins in the Medial Prefrontal Cortex

Fan

Zhong

et al. 2021

Front. Mol. Neurosci.

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The medial prefrontal cortex (mPFC), a key part of the brain networks that are closely related to the regulation of behavior, acts as a key regulator in emotion, social cognition, and decision making. Astrocytes are the majority cell type of glial cells, which play a significant role in a number of processes and establish a suitable environment for the functioning of neurons, including the brain energy metabolism. Astrocyte’s dysfunction in the mPFC has been implicated in various neuropsychiatric disorders. Glucose is a major energy source in the brain. In glucose metabolism, part of glucose is used to convert UDP-GlcNAc as a donor molecule for O-GlcNAcylation, which is controlled by a group of enzymes, O-GlcNAc transferase enzyme (OGT), and O-GlcNAcase (OGA). However, the role of O-GlcNAcylation in astrocytes is almost completely unknown. Our research showed that astrocytic OGT could influence the expression of proteins in the mPFC. Most of these altered proteins participate in metabolic processes, transferase activity, and biosynthetic processes. GFAP, an astrocyte maker, was increased after OGT deletion. These results provide a framework for further study on the role of astrocytic OGT/O-GlcNAcylation in the mPFC.

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Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Astrocytic O-GlcNAc Transferase-Related Proteins in the Medial Prefrontal Cortex

Fan

Zhong

et al. 2021

Front. Mol. Neurosci.

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“…Recent work proposes the dynamic form of intracellular protein glycosylation, O-linked N-Acetylglucosamine (O-GlcNAc), as an attractive target for regulating aging-specific synaptic and plasticity-related molecular alterations, as well as neurodegenerative phenotypes [6][7][8][9][10][11]. O-GlcNAcylation is regulated by two enzymes-O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA)-which catalyze the addition and removal of O-GlcNAc to serine and threonine residues of proteins, respectively.…”

Section: Introductionmentioning

confidence: 99%

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

et al. 2019

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Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation.

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“…The posttranslational modification O-linked β- N-a cetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, is quickly emerging as a potent regulator of brain aging ( 15 – 17 ). Recently, we identified age-related changes in O-GlcNAcylation associated with neuronal dysfunction in old mice ( 17 ).…”

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confidence: 99%

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

White

Fan

Maynard

et al. 2020

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

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Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc–specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.

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O-GlcNAc cycling in the developing, adult and geriatric brain

Cited by 28 publications

References 239 publications

Proteomic Profiling of Astrocytic O-GlcNAc Transferase-Related Proteins in the Medial Prefrontal Cortex

Proteomic Profiling of Astrocytic O-GlcNAc Transferase-Related Proteins in the Medial Prefrontal Cortex

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

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