MassIVE MSV000087160

Partial Public PXD025162

In-depth site-specific O-glycosylation analysis of glycoproteins and endogenous peptides in cerebrospinal fluid (CSF) from healthy individual mild cognitive impairment (MCI) and Alzheimer disease (AD) patients

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Description

Site-specific O-glycoproteome mapping in complex biological system provides molecular basis for understanding the structure-function relationships of glycoproteins and their roles in physiological and pathological processes. Previous O-glycoproteome analysis in cerebrospinal fluid (CSF) focused on sialylated glycoforms, and many CSF glycoproteins have not been characterized comprehensively with respect to their O-glycosylation. In order to provide an unbiased O-glycosylation profiling, we have developed an integrated strategy combining universal boronic acid enrichment, high-pH fractionation, and electron-transfer and higher-energy collision dissociation (EThcD) for improved intact O-glycopeptide analysis. This strategy was applied to analyze O-glycoproteome in CSF, leading to identifications of 308 O-glycopeptides from 110 O-glycoproteins, covering both sialylated and non-sialylated glycoforms. To our knowledge, this is the largest number of O-glycoproteins and O-glycosites reported for CSF so far, including 154 novel O-glycosites. Due to a lack of peptidomics workflow that could incorporate glycosylation analysis, the glycosylation state of CSF endogenous peptides has not been comprehensively studied. Here, we developed a peptidomics workflow that utilizes the EThcD fragmentation and a three-step database searching strategy, allowing both N-glycosylation and O-glycosylation, as well as other common peptide PTMs, to be analyzed at the same time. Interestingly, among the 1492 endogenous peptides identified, 95 of them were O-glycosylated and only 1 N-glycosylated peptide was found, indicating CSF endogenous peptides were preferentially O-glycosylated. By referring to human neuropeptide database, 15 of them were actually O-glycosylated neuropeptides deriving from ProSAAS and secretogranin-1. O-glycoproteome and endogenous peptidome PTMs analysis were also conducted in MCI and AD patients to give a landscape picture of glycosylation in these disease states. The results showed that a decreased fucosylation trend was found in MCI and AD, suggesting its potential relation to the progression of AD. [doi:10.25345/C5WC0C] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CSF ; Alzheimer's disease ; O-glycosylation

Contact

Principal Investigators:
(in alphabetical order) 		Lingjun Li, University of Wisconsin-Madison, United States
Submitting User: LiLab_UWMadison

Publications

Chen Z, Wang D, Yu Q, Johnson J, Shipman R, Zhong X, Huang J, Yu Q, Zetterberg H, Asthana S, Carlsson C, Okonkwo O, Li L.
In-Depth Site-Specific O-Glycosylation Analysis of Glycoproteins and Endogenous Peptides in Cerebrospinal Fluid (CSF) from Healthy Individuals, Mild Cognitive Impairment (MCI), and Alzheimer's Disease (AD) Patients.
ACS Chem Biol. 2022 Nov 18;17(11):3059-3068. Epub 2021 Dec 29.

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