skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease

Abstract

Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brains with and without Alzheimer’s using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. 128 O-GlcNAc peptides covering 78 proteins were altered significantly in Alzheimer’s brain as compared to controls (q<0.05). Moreover, alteration of the O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2]; ORCiD logo [1]
  1. Biological Sciences Division, Pacific Northwest National Laboratory, Richland WA USA
  2. New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York USA
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1378037
Report Number(s):
PNNL-SA-119241
Journal ID: ISSN 0022-3417; 48135; 48666; 453040220
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Journal of Pathology
Additional Journal Information:
Journal Volume: 243; Journal Issue: 1; Journal ID: ISSN 0022-3417
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory

Citation Formats

Wang, Sheng, Yang, Feng, Petyuk, Vladislav A., Shukla, Anil K., Monroe, Matthew E., Gritsenko, Marina A., Rodland, Karin D., Smith, Richard D., Qian, Wei-Jun, Gong, Cheng-Xin, and Liu, Tao. Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease. United States: N. p., 2017. Web. doi:10.1002/path.4929.
Wang, Sheng, Yang, Feng, Petyuk, Vladislav A., Shukla, Anil K., Monroe, Matthew E., Gritsenko, Marina A., Rodland, Karin D., Smith, Richard D., Qian, Wei-Jun, Gong, Cheng-Xin, & Liu, Tao. Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease. United States. doi:10.1002/path.4929.
Wang, Sheng, Yang, Feng, Petyuk, Vladislav A., Shukla, Anil K., Monroe, Matthew E., Gritsenko, Marina A., Rodland, Karin D., Smith, Richard D., Qian, Wei-Jun, Gong, Cheng-Xin, and Liu, Tao. Fri . "Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease". United States. doi:10.1002/path.4929.
@article{osti_1378037,
title = {Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease: Brain protein O-GlcNAcylation in Alzheimer's disease},
author = {Wang, Sheng and Yang, Feng and Petyuk, Vladislav A. and Shukla, Anil K. and Monroe, Matthew E. and Gritsenko, Marina A. and Rodland, Karin D. and Smith, Richard D. and Qian, Wei-Jun and Gong, Cheng-Xin and Liu, Tao},
abstractNote = {Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brains with and without Alzheimer’s using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. 128 O-GlcNAc peptides covering 78 proteins were altered significantly in Alzheimer’s brain as compared to controls (q<0.05). Moreover, alteration of the O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.},
doi = {10.1002/path.4929},
journal = {Journal of Pathology},
issn = {0022-3417},
number = 1,
volume = 243,
place = {United States},
year = {2017},
month = {7}
}

Works referenced in this record:

Tandem Mass Tags:  A Novel Quantification Strategy for Comparative Analysis of Complex Protein Mixtures by MS/MS
journal, April 2003

  • Thompson, Andrew; Schäfer, Jürgen; Kuhn, Karsten
  • Analytical Chemistry, Vol. 75, Issue 8
  • DOI: 10.1021/ac0262560

Quantification of O-glycosylation stoichiometry and dynamics using resolvable mass tags
journal, July 2010

  • Rexach, Jessica E.; Rogers, Claude J.; Yu, Seok-Ho
  • Nature Chemical Biology, Vol. 6, Issue 9
  • DOI: 10.1038/nchembio.412

Global Identification and Characterization of Both O -GlcNAcylation and Phosphorylation at the Murine Synapse
journal, May 2012

  • Trinidad, Jonathan C.; Barkan, David T.; Gulledge, Brittany F.
  • Molecular & Cellular Proteomics, Vol. 11, Issue 8
  • DOI: 10.1074/mcp.O112.018366

Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets
journal, April 2012

  • Alfaro, J. F.; Gong, C. -X.; Monroe, M. E.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 19
  • DOI: 10.1073/pnas.1200425109

MASIC: A software program for fast quantitation and flexible visualization of chromatographic profiles from detected LC–MS(/MS) features
journal, June 2008


Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
journal, December 2008

  • Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A.
  • Nature Protocols, Vol. 4, Issue 1
  • DOI: 10.1038/nprot.2008.211

pLogo: a probabilistic approach to visualizing sequence motifs
journal, October 2013

  • O'Shea, Joseph P.; Chou, Michael F.; Quader, Saad A.
  • Nature Methods, Vol. 10, Issue 12
  • DOI: 10.1038/nmeth.2646

Analysis and Optimization of Copper-Catalyzed Azide–Alkyne Cycloaddition for Bioconjugation
journal, December 2009

  • Hong, Vu; Presolski, Stanislav I.; Ma, Celia
  • Angewandte Chemie International Edition, Vol. 48, Issue 52
  • DOI: 10.1002/anie.200905087

PhosphoSitePlus, 2014: mutations, PTMs and recalibrations
journal, December 2014

  • Hornbeck, Peter V.; Zhang, Bin; Murray, Beth
  • Nucleic Acids Research, Vol. 43, Issue D1
  • DOI: 10.1093/nar/gku1267

Alzheimer Mechanisms and Therapeutic Strategies
journal, March 2012


Proteogenomics connects somatic mutations to signalling in breast cancer
journal, May 2016

  • Mertins, Philipp; Mani, D. R.; Ruggles, Kelly V.
  • Nature, Vol. 534, Issue 7605
  • DOI: 10.1038/nature18003

limma powers differential expression analyses for RNA-sequencing and microarray studies
journal, January 2015

  • Ritchie, Matthew E.; Phipson, Belinda; Wu, Di
  • Nucleic Acids Research, Vol. 43, Issue 7
  • DOI: 10.1093/nar/gkv007

Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer
journal, July 2016


O-Linked-N-acetylglucosamine on extracellular protein domains mediates epithelial cell–matrix interactions
journal, September 2011

  • Sakaidani, Yuta; Nomura, Tomoko; Matsuura, Aiko
  • Nature Communications, Vol. 2, Issue 1
  • DOI: 10.1038/ncomms1591

A two-layered machine learning method to identify protein O-GlcNAcylation sites with O-GlcNAc transferase substrate motifs
journal, January 2015


A probability-based approach for high-throughput protein phosphorylation analysis and site localization
journal, September 2006

  • Beausoleil, Sean A.; Villén, Judit; Gerber, Scott A.
  • Nature Biotechnology, Vol. 24, Issue 10
  • DOI: 10.1038/nbt1240

Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides
journal, May 2009

  • Chalkley, R. J.; Thalhammer, A.; Schoepfer, R.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 22
  • DOI: 10.1073/pnas.0900288106

Statistical significance for genomewide studies
journal, July 2003

  • Storey, J. D.; Tibshirani, R.
  • Proceedings of the National Academy of Sciences, Vol. 100, Issue 16, p. 9440-9445
  • DOI: 10.1073/pnas.1530509100

Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics
journal, May 2007

  • Khidekel, Nelly; Ficarro, Scott B.; Clark, Peter M.
  • Nature Chemical Biology, Vol. 3, Issue 6
  • DOI: 10.1038/nchembio881

Extensive Crosstalk Between O-GlcNAcylation and Phosphorylation Regulates Cytokinesis
journal, January 2010


Reversed-phase chromatography with multiple fraction concatenation strategy for proteome profiling of human MCF10A cells
journal, April 2011


MS-GF+ makes progress towards a universal database search tool for proteomics
journal, October 2014

  • Kim, Sangtae; Pevzner, Pavel A.
  • Nature Communications, Vol. 5, Issue 1
  • DOI: 10.1038/ncomms6277

Epigenetic Alterations in Alzheimer’s Disease
journal, December 2015