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The emerging link between O-GlcNAcylation and neurological disorders

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Abstract

O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is involved in the regulation of many cellular cascades and neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. In the brain, the expression of O-GlcNAcylation is notably heightened, as is that of O-linked N-acetylglucosaminyltransferase (OGT) and β-N-acetylglucosaminidase (OGA), the presence of which is prominent in many regions of neurological importance. Most importantly, O-GlcNAcylation is believed to contribute to the normal functioning of neurons; conversely, its dysregulation participates in the pathogenesis of neurological disorders. In neurodegenerative diseases, O-GlcNAcylation of the brain’s key proteins, such as tau and amyloid-β, interacts with their phosphorylation, thereby triggering the formation of neurofibrillary tangles and amyloid plaques. An increase of O-GlcNAcylation by pharmacological intervention prevents neuronal loss. Additionally, O-GlcNAcylation is stress sensitive, and its elevation is cytoprotective. Increased O-GlcNAcylation ameliorated brain damage in victims of both trauma-hemorrhage and stroke. In this review, we summarize the current understanding of O-GlcNAcylation’s physiological and pathological roles in the nervous system and provide a foundation for development of a therapeutic strategy for neurological disorders.

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Abbreviations

Aβ:

β-Amyloid peptide

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AICD:

Amyloid precursor protein intracellular domain

APP:

Amyloid precursor protein

Bad:

BCL2-associated agonist of cell death

BAX:

BCL2 associated X

BEMAD:

Michael addition with dithiothreitol

CDK5:

Cyclin-dependent kinase 5

CSF:

Cerebral spinal fluid

eNOS:

Endothelial nitric oxide synthase

ETD:

Electron-transfer dissociation

GalT:

β1-4-Galactosyltransferase

GFAT:

l-Glutamine:fructose-6-phosphate amidotransferase

GlcN:

Glucosamine

HAT:

Histone acetyltransferase

HBP:

Hexosamine biosynthetic pathway

HD:

Huntington’s disease

ICH:

Intracerebral hemorrhage

LC:

Liquid chromatography

IKK:

Inhibitor of nuclear factor κB kinase

IκB:

Inhibitor of nuclear factor κB

I/R:

Ischemia/reperfusion

MAP:

Microtubule-associated protein

MGEA5:

Meningioma expressed antigen 5

mOGT:

Mitochondrial OGT

MS:

Mass spectrometry

NButGT:

1,2-Dideoxy-2′-propyl-alpha-d-glucopyranoso-[2,1-d]-Delta 2′-thiazoline

ncOGA:

Nuclear and cytoplasmic OGA

ncOGT:

Nucleocytoplasmic OGT

NFTs:

Neurofibrillary tangles

NLS:

Nuclear localization signal

NO:

Nitric oxide

OGA:

β-N-Acetylglucosaminidase

nNOS:

Neuronal nitric oxide synthase

O-GlcNAcylation:

O-linked β-N-acetylglucosaminylation

OGT:

O-linked N-acetylglucosaminyltransferase

PD:

Parkinson’s disease

PKAcs:

Protein kinase A catalytic subunit

PFK1:

Phosphofructokinase 1

PHFs:

Paired helical filaments

PUGNAc:

O-(2-Acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate

RPLC:

Reversed-phase liquid chromatography

sAPPβ:

Soluble amyloid precursor protein β

SOD1:

Superoxide dismutase 1

sOGA:

Short-form OGA

sOGT:

Short OGT

Stat:

Signal transducer and activator of transcription

TPR:

Tetratricopeptide

YY1:

Yin Yang 1

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81571600, 81322018 and 81273287 to J.W.H., and 81401361 to X.F.M.) and the Youth Top-notch Talent Support Program (to J.W.H.).

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  1. Xiaofeng Ma and He Li contributed equally to this work.

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  1. Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Xiaofeng Ma, He Li, Yating He & Junwei Hao

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Ma, X., Li, H., He, Y. et al. The emerging link between O-GlcNAcylation and neurological disorders. Cell. Mol. Life Sci. 74, 3667–3686 (2017). https://doi.org/10.1007/s00018-017-2542-9

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