Review
Role and therapeutic implications of protein glycosylation in neuroinflammation

https://doi.org/10.1016/j.molmed.2022.01.004Get rights and content

Highlights

  • The complexity of neuroinflammation associated with all central nervous system (CNS) disorders remains a major obstacle for their complete understanding and therapeutic targeting, because multiple molecular mechanisms remain overlooked.

  • The study of changes in glycosylation (i.e., post-translational addition of glycans to protein backbones) upon neuroinflammation is gaining increased interest.

  • Dysregulations in the glycophenotype of CNS disorders can help to identify targets to be addressed by newly developed glyco-based therapeutics.

  • Targeting the glycome is a daunting task because it is highly flexible, dynamic, and nontemplate driven, involving multiple players.

  • Small molecules targeting the glycome, such as glycosylation inhibitors, glycan-based residues, glycomimetics, glycosylation enzymes, and glycan-binding proteins, are attractive candidates to be used in the future as therapeutics in the CNS.

The importance of glycosylation (post-translational attachment of glycan residues to proteins) in the context of neuroinflammation is only now beginning to be understood. Although the glycome is challenging to investigate due to its complexity, this field is gaining interest because of the emergence of novel analytical methods. These investigations offer the possibility of further understanding the molecular signature of disorders with underlying neuroinflammatory cascades. In this review, we portray the clinically relevant trends in glyconeurobiology and suggest glyco-related paths that could be targeted therapeutically to decrease neuroinflammation. A combinatorial insight from glycobiology and neurology can be harnessed to better understand neuroinflammatory-related conditions to identify relevant molecular targets.

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

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