Trends in Molecular Medicine
ReviewRole and therapeutic implications of protein glycosylation in neuroinflammation
Section snippets
Neuroinflammation and glycosylation: the underexplored relationship
Neuroinflammation is broadly described as the inflammatory cascades that take place in either the peripheral nervous system (PNS) or the central nervous system (CNS), combining both immune and nervous systems, which makes it a complex concept still imperfectly understood [1,2]. In the CNS, neuroinflammation is associated with damage or disorders that can be caused by a direct penetrating physical injury [such as traumatic brain injury (TBI) or spinal cord injury (SCI)], or that arise from
Protein glycosylation modulation in neuroinflammatory-related neurological conditions
Over the past two decades, glycans have gained increasing attention in the CNS (Box 1) since they are reported to have roles in diverse chief functions, such as neural development, synapse establishment and stabilisation, neurite outgrowth and synaptic plasticity (reviewed in [11., 12., 13.]). The main mammalian glycan classes and types of glycosylation are illustrated (see Figure I in Box 1).
Protein glycosylation specifically is a major player in CNS homeostasis, accounting for the increasing
Glycan-binding proteins as immune cell check points in neuroinflammatory-related neurological conditions
When looking at changes in protein glycosylation in the context of neuroinflammation, other players are involved (besides the glycans themselves), the action of which should also be explored. This is the case with GBPs, which include recognition receptors in immune cells, and commonly lead to the initiation of pro- or anti-inflammatory cascades. Such proteins can be divided into antibodies and lectins, with the latter being of particular interest in the CNS, mainly in microglia. Lectins are
Tackling glycodysregulations in the CNS: therapeutic implications
After carrying out an in-depth characterisation of the glycoprofile in each CNS condition, the next step would be to target the dysregulations seen through the delivery (as a bolus or in a vehicle) of glyco-related active ingredients (Figure 2, Key figure). Various approaches could be explored to promote or inhibit specific glycosylation modulation to tune the glycome toward a physiologically healthy glycophenotype. However, since the knowledge of each disease glycomic profile remains limited,
Concluding remarks
The role of proteomics and genomics and their contribution to our understanding of pathophysiological conditions have been a focus of research in recent decades. However, the importance of glycomics in these contexts has only recently gained visibility. Despite the struggle to target glycodysregulations in the CNS (see Outstanding questions), the importance and relevance of targeting the glycome in pathological conditions are underlined by the clinical trials currently using small-molecule
Acknowledgments
This publication was supported by the BrainMatTrain project funded by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Initial Training Network and Grant Agreement No. 676408. This work also had the financial support of Science Foundation Ireland (SFI), co-funded under the European Regional Development Fund under Grant Number 13/RC/2073_P2. Furthermore, this project has received funding from the European Union’s Horizon 2020 Research and
Declaration of interests
None declared by authors.
Glossary
- Alzheimer’s disease (AD)
- the most common neurodegenerative disease and cause of dementia worldwide, primarily characterised by cognitive functioning loss due to progressive and irreversible neuronal death. This derives from toxicity elicited by the deposition of β-amyloid plaques [derived, in turn, from amyloid precursor protein (APP)] and neurofibrillary hyperphosphorylated tau tangles [121], which leads to synaptic loss.
- Amyotrophic lateral sclerosis (ALS)
- neurodegenerative disorder in which
References (127)
Sweet tailoring of glyco-modulatory extracellular matrix-inspired biomaterials to target neuroinflammation
Cell Reports Phys. Sci.
(2021)- et al.
Neuroinflammation in Parkinson’s disease: a target for neuroprotection?
Lancet Neurol.
(2009) N-glycan processing deficiency promotes spontaneous inflammatory demyelination and neurodegeneration
J. Biol. Chem.
(2007)Inflammation and neurodegenerative diseases
Am. J. Clin. Nutr.
(2006)A comprehensive glycome profiling of Huntington’s disease transgenic mice
Biochim. Biophys. Acta Gen. Subj.
(2015)Reactivity of anti-HNK-1 antibodies to branched O-mannose glycans associated with demyelination
Biochem. Biophys. Res. Commun.
(2017)Diminished O-GlcNAcylation in Alzheimer’s disease is strongly correlated with mitochondrial anomalies
Biochim. Biophys. Acta Mol. basis Dis.
(2019)Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults
Brain Behav. Immun.
(2017)CSF N-glycoproteomics for early diagnosis in Alzheimer’s disease
J. Proteome
(2016)Chondroitinase treatment following spinal contusion injury increases migration of oligodendrocyte progenitor cells
Exp. Neurol.
(2011)
Rapid trimming of cell surface polysialic acid (PolySia) by exovesicular sialidase triggers release of preexisting surface neurotrophin
J. Biol. Chem.
Tumor necrosis factor
Cancer Lett.
Glycosylation and integrin regulation in cancer
Trends Cancer
Array-based functional screening of heparin glycans
Chem. Biol.
Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer’s disease brain, serum and cerebrospinal fluid towards potential biomarker discovery
Biochim. Biophys. Acta Gen. Subj.
O-GlcNAc glycosylation of p27kip1 promotes astrocyte migration and functional recovery after spinal cord contusion
Exp. Cell Res.
A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR: subunit organization and binding to multivalent ligands
J. Biol. Chem.
The role of selectins in inflammation and disease
Trends Mol. Med.
Differential expression of selectins by mouse brain capillary endothelial cells in vitro in response to distinct inflammatory stimuli
Neurosci. Lett.
Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration
Immunity
Microglia-secreted galectin-3 acts as a Toll-like receptor 4 ligand and contributes to microglial activation
Cell Rep.
Integration of lectin–glycan recognition systems and immune cell networks in CNS inflammation
Cytokine Growth Factor Rev.
Neuroinflammation: the devil is in the details
J. Neurochem.
Neuroinflammation in the peripheral nerve: cause, modulator, or bystander in peripheral neuropathies?
Glia
Neuroinflammation as a common feature of neurodegenerative disorders
Front. Pharmarcol.
Interplay between age and neuroinflammation in multiple sclerosis: effects on motor and cognitive functions
Front. Aging Neurosci.
Innate immunity and neuroinflammation
Mediat. Inflamm.
Immunobiology: The immune system in health and disease
Review: microglia of the aged brain: primed to be activated and resistant to regulation
Neuropathol. Appl. Neurobiol.
Glycosylation and the immune system
Science.
The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans
Nat. Rev. Drug Discov.
N-glycosylation in regulation of the nervous system
Adv. Neurobiol.
The role of protein N-glycosylation in neural transmission
Glycobiology
Glycans and neural cell interactions
Nat. Rev. Neurosci.
Extracellular matrix of the central nervous system: from neglect to challenge
Histochem. Cell Biol.
Extracellular matrixes and neuroinflammation
BMB Rep.
Absence of Neu5Gc and presence of anti-Neu5Gc antibodies in humans—an evolutionary perspective
Front. Immunol.
Characteristics of α-Gal epitope, anti-Gal antibody, α1,3 galactosyltransferase and its clinical exploitation (Review)
Int. J. Mol. Med.
Lipolysaccharide-induced neuroinflammation is associated with Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration in rats
Adv. Alzheimers Dis.
Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Nat. Commun.
CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG
J. Exp. Med.
Mgat5 deficiency in T cells and experimental autoimmune encephalomyelitis
ISRN Neurol.
Protective effect of N -glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer’s disease
Glycobiology
The N-glycan profile in cortex and hippocampus is altered in Alzheimer disease
J. Neurochem.
Loss of branched O-mannosyl glycans in astrocytes accelerates remyelination
J. Neurosci.
Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production
J. Biochem.
O-GlcNAc regulation of autophagy and α-synuclein homeostasis; implications for Parkinson’s disease
Mol. Brain
Neuroinflammation and protein pathology in Parkinson’s disease dementia
Acta Neuropathol. Commun.
Serum N-glycosylation in Parkinson’s disease: a novel approach for potential alterations
Molecules
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