Cell Metab new brain glycogen function

Written by Wenqiang Chen | Glycosylation is an important post-translational modification of proteins in organisms
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2% of human genes are related to sugar metabolism, and mutations in these genes are closely related to more than one hundred human diseases [1-2]
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Glycosylation defects are an important feature of many neurological diseases, because N-glycosylation sites play an important role in regulating important biological functions such as synaptic plasticity, axon growth and neuron morphology
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In order to better understand the molecular characteristics of brain-specific N-glucose metabolism, on May 26, 2021, researchers from the University of Kentucky in the United States published an online publication entitled Brain glycogen serves as a critical glucosamine cache required for protein in Cell metabolism.
Glycosylation research papers, through techniques such as isotope tracing and mass spectrometry, discovered that glucosamine is a rich substitute for brain glycogen and can act as a natural buffer for a variety of sugar complexes, thus revealing that brain glycogen is involved in protein glycosylation.
Important biological role
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First, the researchers isolated and purified glycogen from a variety of mouse tissues.
After the glycosidic bond was hydrolyzed, the monomer components of the sugar were analyzed using gas chromatography-mass spectrometry (Figure 1)
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The glycogen in the muscle and liver of mice contains 1% and 0.
1% glucosamine respectively, while the glycogen in the brain contains up to 25% glucosamine
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Subsequently, the researchers carried out isotope tracing experiments on primary astrocytes to reveal an alternative source of intracellular glucosamine, so it is believed that the glucosamine synthesized from glucose may be the source of intracellular glucosamine
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This hypothesis was verified by the 13C6 labeled glucose tracer
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In vitro experiments using mouse brains fed with 13C6 labeled glucose tracer also verified this conclusion
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Figure 1.
Glucosamine is the natural monomer of brain glycogen.
Researchers subsequently proved through in vitro experiments that UDP-glucosamine is one of the substrates of glycogen synthase (GYS), and revealed that glucosamine is derived from GYS through structural chemical means.
The mechanism of direct incorporation into glycogen
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Knockdown experiments in vitro also proved that the glycogenolytic effect of glucosamine was mediated by glycogen phosphorylase (GP)
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The researchers further revealed that glycogen-derived glucosamine is an important precursor metabolite for the production of GlcNAc and N-sugar through in vitro knockdown experiments combined with metabolic analysis and isotope tracing technology (Figure 2)
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Figure 2.
Researchers reveal the mechanism of free flow of metabolites between glycogen and N-linked glycans.
So, how can brain glycosylation disorders lead to brain diseases? It is known that shikonin, encoded by the EPM2A gene, is a glycogen phosphatase involved in glycogen metabolism.
The functional defect of this enzyme is related to a kind of neurodegenerative epilepsy in children, and children usually die within ten years of onset
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Researchers used shikonin knockout mice to study the pathological mechanism of protein glycosylation defects and found that brain regions with high levels of polydextran lack sufficient glucosamine to convert into glycosylated proteins.
This condition is accompanied by Endoplasmic reticulum stress and neuroinflammation appear, and enzymatic hydrolysis of polyglucan bodies can alleviate the degree of low glycosylation, thereby alleviating the pathological characteristics (Figure 3)
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Figure 3.
Abnormal glycosylation can lead to N-glycan metabolism and neurodegeneration.
This article demonstrates that glucosamine can be used in three different ways-free metabolic form, glycogen-bound form, and branched glycan and polyglycan.
The mannose chain form reveals that the interaction between these three forms of glucosamine plays an important role in maintaining the brain's metabolic homeostasis
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Glucosamine produced by glycogen can act as a key buffer under stress stimuli and other conditions, thereby helping us cope with multiple pathological conditions such as aging and traumatic brain injury
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Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
05.
003.
Plate maker: Eleven References [1] Narimatsu, Y.
, Joshi, HJ, Nason, R.
, Van Coillie, J.
, Karlsson, R.
, Sun, L.
, Ye, Z.
, Chen, YH, Schjoldager, KT, and Steentoft, C.
(2019).
An atlas of human glycosylation pathways enables display of the human glycome by gene engineered cells.
Mol.
Cell 75, 394–407.
e5.
[2] Ng, BG, and Freeze, HH (2018).
Perspectives on glycosylation and its congenital disorders.
Trends Genet 34, 466–476.
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