Glycoproteomics in neurodegenerative diseases

Abstract

Protein glycosylation regulates protein function and cellular distribution. Additionally, aberrant protein glycosylations have been recognized to play major roles in human disorders, including neurodegenerative diseases. Glycoproteomics, a branch of proteomics that catalogs and quantifies glycoproteins, provides a powerful means to systematically profile the glycopeptides or glycoproteins of a complex mixture that are highly enriched in body fluids, and therefore, carry great potential to be diagnostic and/or prognostic markers. Application of this mass spectrometrybased technology to the study of neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease) is relatively new, and is expected to provide insight into the biochemical pathogenesis of neurodegeneration, as well as biomarker discovery. In this review, we have summarized the current understanding of glycoproteins in biology and neurodegenerative disease, and have discussed existing proteomic technologies that are utilized to characterize glycoproteins. Some of the ongoing studies, where glycoproteins isolated from cerebrospinal fluid and human brain are being characterized in Parkinson's disease at different stages versus controls, are presented, along with future applications of targeted validation of brain specific glycoproteins in body fluids.

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

“…Proteomics Data Mining for PD-related Proteins/Peptides-Proteomic data were gathered from our previous quantitative PD-related proteomic studies, including a general human CSF profiling (19), two general human midbrain profiling studies (20,21), general human frontal cortex profiling studies of PD progression (22)(23)(24), glycoprotein profiling studies of human CSF and frontal cortex (25), a phosphoprotein profiling of human frontal cortex (unpublished data), glyco-and phospho-protein profiling studies in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model (putamen; unpublished data). A total of 15 data sets were integrated: two on the human CSF proteome, four on the human midbrain (substantia nigra) proteome, six on the human frontal cortex proteome, and the remaining three on the monkey putamen proteome.…”

Microheterogeneity of some serum glycoproteins in neurodegenerative diseases

“…Few proteins have been identified in which glycosylation appears to be important in the disease processes of AD and PD [25]. In AD patients, an increased ratio of the hexasialo-Tf to the less sialylated isoform was detected in the Tf C1 phenotype [28], as well as hyperglycosylated microtubule-associated protein tau [29] or proteins in neural plaques [30].…”

“…It influences the biological activity of proteins and affects their folding and stability [25]. Incomplete glycosylation leads to faster clearance of a protein from the circulation and is thus a speculated contributor to human disorders, including neurodegenerative diseases [26]; the study of glycosylation degree/type is increasingly important for diagnosis and treatment.…”

Energy-resolved collision-induced dissociation pathways of model N-linked glycopeptides: implications for capturing glycan connectivity and peptide sequence in a single experiment

“…and human disease states (e.g., cancer; congenital disorders of glycosylation; neurodegenerative disorders, etc.). [6][7][8][9][10][11][12][13][14][15][16][17] While protein glycosylation analyses are oen carried out with either a "glycocentric" (i.e., compositional and structural analysis of glycans released from glycoproteins) or a "proteocentric" (i.e., identication of deglycosylated glycoproteins with indirect glycosylation site localization) outlook, the loss of molecular detail imposed by glycan release limits the specicity and potential for biological resolution that can be furnished by such analyses. 18 In order to map specic oligosaccharide structures to their corresponding sites of protein attachment, the analytical scheme must preserve the oligosaccharide-polypeptide connectivity until such a time that the chosen approach can characterize the linkage.…”