Glycomic and Glycoproteomic Techniques in Neurodegenerative Disorders and Neurotrauma: Towards Personalized Markers

Abstract

The proteome represents all the proteins expressed by a genome, a cell, a tissue, or an organism at any given time under defined physiological or pathological circumstances. Proteomic analysis has provided unparalleled opportunities for the discovery of expression patterns of proteins in a biological system, yielding precise and inclusive data about the system. Advances in the proteomics field opened the door to wider knowledge of the mechanisms underlying various post-translational modifications (PTMs) of proteins, including glycosylation. As of yet, the role of most of these PTMs remains unidentified. In this state-of-the-art review, we present a synopsis of glycosylation processes and the pathophysiological conditions that might ensue secondary to glycosylation shortcomings. The dynamics of protein glycosylation, a crucial mechanism that allows gene and pathway regulation, is described. We also explain how-at a biomolecular level-mutations in glycosylation-related genes may lead to neuropsychiatric manifestations and neurodegenerative disorders. We then analyze the shortcomings of glycoproteomic studies, putting into perspective their downfalls and the different advanced enrichment techniques that emanated to overcome some of these challenges. Furthermore, we summarize studies tackling the association between glycosylation and neuropsychiatric disorders and explore glycoproteomic changes in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington disease, multiple sclerosis, and amyotrophic lateral sclerosis. We finally conclude with the role of glycomics in the area of traumatic brain injury (TBI) and provide perspectives on the clinical application of glycoproteomics as potential diagnostic tools and their application in personalized medicine.

Keywords: glycosylation; neurodegenerative diseases; neuropsychiatric disorders; post-translational modifications; proteomics.

Figure 1

A depiction of the nomenclature, topology, and glycosylation patterns of N- and O-glycans. (A) Linkage of N-acetylglucosamine to asparagine amino acid via an N-linked bond, followed by linkage of N-acetylgalactosamine to serine or threonine amino acids via an O-linked bond. The glycoprotein shown is a transmembrane protein. The possible bonds formed between glycan residues are illustrated. (B) The three possible types of N-linked glycosylation products, depicted through transmembrane proteins. GlcNAc: N-acetylglucosamine; Man: mannose; Gal: galactose; NeuNAc/Sia: N-acetylneuraminic acid/sialic acid; Fuc: fucose.

Figure 2

Correlation between glycosylation changes and CNS diseases. (A) Depiction of the consequences of glycosylation defects occurring in the different lobes of the human brain. (B) Characterization of consequences of altered glycosylation based on the type of neurological or psychiatric disease formed.

Figure 3

An overview of the after-effects of TBI on the neurological components of the brain, ultimately leading to aberrant glycosylation as shown by MS-based glycoproteomics. TBI: traumatic brain injury, MS: mass spectrometry.

Figure 4

The process of glycosylation of normal PrP and the effect of deficiency in glycosylation or conversion of PrP^C to PrP^Sc. (A) In normal conditions, nascent PrP undergo glycosylation which occurs in the Endoplasmic Reticulum (ER), then it matures in the Golgi apparatus and eventually reaches the plasma with the aid of GPI anchor. However, when glycosylation deficiency occurs, the nascent PrP becomes insoluble aggregates which leads to early or late apoptosis (green label). (B) Mature PrP^C at the level of the plasma may interact with PrP^Sc, and this would lead to a conversion and accumulation of PrP^Sc which in turn would increase the level of cytotoxicity due to the presence of this prions disease.