Glycosylation and other PTMs alterations in neurodegenerative diseases: Current status and future role in neurotrauma

Abstract

Traumatic brain injuries (TBIs) present a chief public health threat affecting nations worldwide. As numbers of patients afflicted by TBI are expected to rise, the necessity to increase our understanding of the pathophysiological mechanism(s) as a result of TBI mounts. TBI is known to augment the risk of developing a number of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Hence, it is rational to assume that a common mechanistic ground links the pathophysiology of NDs to that of TBIs. Through this review, we aim to identify the protein-protein interactions, differential proteins expression, and PTMs, mainly glycosylation, that are involved in the pathogenesis of both ND and TBI. OVID and PubMed have been rigorously searched to identify studies that utilized advanced proteomic platforms (MS based) and systems biology tools to unfold the mechanism(s) behind ND in an attempt to unveil the mysterious biological processes that occur postinjury. Various PTMs have been found to be common between TBI and AD, whereas no similarities have been found between TBI and PD. Phosphorylated tau protein, glycosylated amyloid precursor protein, and many other modifications appear to be common in both TBI and AD. PTMs, differential protein profiles, and altered biological pathways appear to have critical roles in ND processes by interfering with their pathological condition in a manner similar to TBI. Advancement in glycoproteomic studies pertaining to ND and TBI is urgently needed in order to develop better diagnostic tools, therapies, and more favorable prognoses.

Keywords: Glycans; Glycomics; Neurodegenerative diseases; PTMs; TBI.

Figure 1

Biochemical structures of different N- and O-glycans. (A) Linkage of N-acetylglucosamine to asparagine amino acid via an N-linked bond. (B) Linkage of N-acetylgalactosamine to serine or threonine amino acids via an O-linked bond.

Figure 2

An overview on the workflow of MS-based glycoproteomics. After taking a brain sample following TBI, several steps are performed to enrich and digest the proteins in order to administer the sample into the MS.

Figure 3

An example on the nomenclature, topology, and glycosylation patterns of glycans. The glycoprotein depicted is an example of a transmembrane protein. The possible bond linkages between glycan residues are shown. GlcNAc: N-acetylglucosamine; Man: mannose; Gal: galactose; NeuNAc/Sia: N-acetylneuraminic acid/sialic acid; Fuc: fucose.

Figure 4

Schematic diagram showing the pathophysiology of TBI and the use of MS to identify different altered glycoproteins. Immediately after TBI, primary injury causes a distortion in the phospholipid bilayer of neural cells resulting in ion influx/efflux through the cell membrane. This is followed within minutes to hours by closure of the defect by lysolecithin to prevent further ion exchange. Subsequently, secondary injury occurs igniting a set of biochemical reactions and cascades that may take several hours to days to manifest. Mass spectrometric analysis is later used to identify and characterize the different altered glycoproteins.