Skip to main content
SpringerLink
Log in

O-GlcNAcylation of Neuronal Proteins: Roles in Neuronal Functions and in Neurodegeneration

  • Chapter
  • First Online:
Glycobiology of the Nervous System

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 9))

Abstract

O-GlcNAc is the attachment of β-N-acetylglucosamine to the hydroxyl group of serine and threonine in nuclear and cytoplasmic proteins. It is generally not further elongated but exists as a monosaccharide that can be rapidly added or removed. Thousands of proteins involved in gene transcription, protein translation, and degradation as well as the regulation of signal transduction contain O-GlcNAc. Brain is one of the tissues where O-GlcNAc is most highly expressed and deletion of neuronal O-GlcNAc leads to death early in development. O-GlcNAc is also important for normal adult brain function, where dynamic processes like learning and memory at least in part depend on the modification of specific proteins by O-GlcNAc. Conversely, too much or too little O-GlcNAc on other proteins participates in neurodegenerative processes underlying diseases such as Alzheimer’s and Parkinson’s. In this chapter, we describe the expression and regulation of O-GlcNAc in the nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Akimoto Y, Comer FI, Cole RN, Kwakami AKH, Hirano H, Hart GW. Localization of the O-GlcNAc transferase and O-GlcNAc-modified proteins in rat cerebellar cortex. Brain Res. 2003;966(2):194–205.

    CAS  PubMed  Google Scholar 

  • Alfaro JF, Gong CX, Monroe ME, Aldrich JT, Clauss TR, Purvine SO, et al. Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. Proc Natl Acad Sci U S A. 2012;109(19):7280–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andrali SS, Qian Q, Ozcan S. Glucose mediates the translocation of NeuroD1 by O-linked glycosylation. J Biol Chem. 2007;282(21):15589–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Arnold SC, Johnson GVW, Cole RN, Dong DLY, Lee M, Hart GW. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem. 1996;271(46):28741–4.

    CAS  PubMed  Google Scholar 

  • Banerjee S, Robbins PW, Samuelson J. Molecular characterization of nucleocytosolic O-GlcNAc transferases of Giardia lamblia and Cryptosporidium parvum. Glycobiology. 2009;19(4):331–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Banerjee PS, Hart GW, Cho JW. Chemical approaches to study O-GlcNAcylation. Chem Soc Rev. 2013;42(10):4345–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Benko DM, Haltiwanger RS, Hart GW, Gibson W. Virion basic phosphoprotein from human cytomegalovirus contains O-linked N-acetylglucosamine. Proc Natl Acad Sci U S A. 1988;85(8):2573–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, et al. Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science. 2000;290(5500):2302–3.

    CAS  PubMed  Google Scholar 

  • Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5(1):64–74.

    PubMed  Google Scholar 

  • Bullen, Hart. AMPK regulates OGT substrate specificity. Forthcoming paper.

    Google Scholar 

  • Butkinaree C, Cheung WD, Park S, Park K, Barbr M, Hart GW. Characterization of beta-N-acetylglucosaminidase cleavage by caspase-3 during apoptosis. J Biol Chem. 2008;283(35):23557–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Caillet-Boudin ML, Strecker G, Michalski JC. O-linked GlcNAc in serotype-2 adenovirus fibre. Eur J Biochem. 1989;184(1):205–11.

    CAS  PubMed  Google Scholar 

  • Carillo LD, Froemming JA, Mahal LK. Targeted in vivo O-GlcNAc sensors reveal discrete compartment-specific dynamics during signal transduction. J Biol Chem. 2011;286(8):6650–8.

    Google Scholar 

  • Cheung WD, Hart GW. AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation. J Biol Chem. 2008;283(19):13009–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cheung WD, Sakabe K, Housley MP, Dias WB, Hart GW. O-linked beta-N-acetylglucosaminyltransferase substrate specificity is regulated by myosin phosphatase targeting and other interacting proteins. J Biol Chem. 2008;283(49):33935–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chou TY, Dang CV, Hart GW. Glycosylation of the c-Myc transactivation domain. Proc Natl Acad Sci U S A. 1995a;92(10):4417–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chou TY, Hart GW, Dang CV. c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem. 1995b;270(32):18961–5.

    CAS  PubMed  Google Scholar 

  • Clark PM, Dweck JF, Mason DE, Hart CR, Buck SB, Peters EC, et al. Direct in-gel fluorescence detection and cellular imaging of O-GlcNAc-modified proteins. J Am Chem Soc. 2008;130(35):11576–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cole RN, Hart GW. Cytosolic O-glycosylation is abundant in nerve terminals. J Neurochem. 2001;79(5):1080–9.

    CAS  PubMed  Google Scholar 

  • Comer FI, Hart GW. O-GlcNAc and the control of gene expression. Biochim Biophys Acta. 1999;1473(1):161–71.

    CAS  PubMed  Google Scholar 

  • Datta B, Ray MK, Chakrabarti D, Wylie DE, Gupta NK. Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) and its possible role in the inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2 alpha-subunit. J Biol Chem. 1989;264(34):20620–4.

    CAS  PubMed  Google Scholar 

  • de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101–13.

    PubMed Central  PubMed  Google Scholar 

  • Dennis RJ, Taylor EJ, Macauley MS, Stubbs KA, Turkenburg JP, Hart SJ, et al. Structure and mechanism of a bacterial beta-glucosaminidase having O-GlcNAcase activity. Nat Struct Mol Biol. 2006;13(4):365–71.

    CAS  PubMed  Google Scholar 

  • Dias WB, Hart GW. O-GlcNAc modification in diabetes and Alzheimer’s disease. Mol Biosyst. 2007;3(11):766–72.

    CAS  PubMed  Google Scholar 

  • Dias WB, Cheung WD, Wang Z, Hart GW. Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc modification. J Biol Chem. 2009;284(32):21327–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dias WB, Cheung WD, Hart GW. O-GlcNAcylation of kinases. Biochem Biophys Res Commun. 2012;422(2):224–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dong DL, Hart GW. Purification and characterization of an O-GlcNAc selective N-acetyl-beta-D-glucosaminidase from rat spleen cytosol. J Biol Chem. 1994;269(30):19321–30.

    CAS  PubMed  Google Scholar 

  • Fang B, Miller MW. Use of galactosyltransferase to assess the biological function of O-linked N-acetyl-d-glucosamine: a potential role for O-GlcNAc during cell division. Exp Cell Res. 2001;263(2):243–53.

    CAS  PubMed  Google Scholar 

  • Fiederling A, Ewert R, Andreyeva A, Jungling K, Gottmann K. E-cadherin is required at GABAergic synapses in cultured cortical neurons. Neurosci Lett. 2011;501(3):167–72.

    CAS  PubMed  Google Scholar 

  • Francisco H, Kollins K, Varghis N, Vocadlo D, Vosseller K, Gallo G. O-GLcNAc post-translational modifications regulate the entry of neurons into an axon branching program. Dev Neurobiol. 2009;69(2–3):162–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fredriksen L, Mathiesen G, Moen A, Bron PA, Kleerebezem M, Eijsink VG, et al. The major autolysin Acm2 from Lactobacillus plantarum undergoes cytoplasmic O-glycosylation. J Bacteriol. 2012;194(2):325–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fujiki R, Hashiba W, Sekine H, Yokoyama A, Chikanishi T, Ito S, et al. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature. 2011;480(7378):557–60.

    CAS  PubMed  Google Scholar 

  • Gao Y, Wells L, Comer FI, Parker GJ, Hart GW. Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem. 2001;276(13):9838–45.

    CAS  PubMed  Google Scholar 

  • Geng F, Zhi W, Anderson RA, Leber B, Andrews DW. Multiple post-translational modifications regulate E-cadherin transport during apoptosis. J Cell Sci. 2012;125(Pt 11):2615–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Grant SG. Synaptopathies: diseases of the synaptome. Curr Opin Neurobiol. 2012;22(3):522–9.

    CAS  PubMed  Google Scholar 

  • Griffith LS, Mathes M, Schmitz B. Beta-amyloid precursor protein is modified with O-linked N-acetylglucosamine. J Neurosci Res. 1995;41(2):270–8.

    CAS  PubMed  Google Scholar 

  • Guinez C, Mir AM, Dehennaut V, Cacan R, Harduin-Lepers A, Michalski JC, et al. Protein ubiquitination is modulated by O-GlcNAc glycosylation. FASEB J. 2008;22(8):2901–11.

    CAS  PubMed  Google Scholar 

  • Haltiwanger RS, Holt GD, Hart GW. Enzymatic addition of O-GlcNAc to nuclear and cytoplasmic proteins. Identification of a uridine diphospho-N-acetylglucosamine:peptide beta-N-acetylglucosaminyltransferase. J Biol Chem. 1990;265(5):2563–8.

    CAS  PubMed  Google Scholar 

  • Haltiwanger RS, Blomberg MA, Hart GW. Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylglucosaminyltransferase. J Biol Chem. 1992;267(13):9005–13.

    CAS  PubMed  Google Scholar 

  • Hanley JG. AMPA receptor trafficking pathways and links to dendritic spine morphogenesis. Cell Adh Migr. 2008;2(4):276–82.

    PubMed Central  PubMed  Google Scholar 

  • Hanover JA, Song Y, Lubas WB, Shin SH, Ragano-Caracciola M, Kochran J, et al. Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys. 2003;409(2):287–97.

    CAS  PubMed  Google Scholar 

  • Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007;26(7139):1017–22.

    Google Scholar 

  • Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O. Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011;80:825–58.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heckel D, Comtesse N, Brass N, Blin N, Zang KD, Meese E. Novel immunogenic antigen homologous to hyaluronidase in meningioma. Hum Mol Genet. 1998;7(12):1859–72.

    CAS  PubMed  Google Scholar 

  • Holt GD, Hart GW. The subcellular distribution of terminal N-acetylglucosamine moieties. Localization of a novel protein-saccharide linkage, O-linked GlcNAc. J Biol Chem. 1986;26(17):8049–57.

    Google Scholar 

  • Holt GD, Snow CM, Senior A, Haltiwanger RS, Gerace L, Hart GW. Nuclear pore complex glycoproteins contain cytoplasmically disposed O-linked N-acetylglucosamine. J Cell Biol. 1987;104(5):1157–64.

    CAS  PubMed  Google Scholar 

  • Housley MP, Udeshi ND, Rodgers JT, Shabanowitz J, Puigserver P, Hunt DF, et al. A PGC-1alpha-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J Biol Chem. 2009;284(8):5148–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jang H, Kim TW, Yoon S, Choi SY, Kang TW, Kim SY, et al. O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell. 2012;11(1):62–74.

    CAS  PubMed  Google Scholar 

  • Jinek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol. 2004;11(10):1001–7.

    CAS  PubMed  Google Scholar 

  • Kanno T, Yaguchi T, Nagata T, Mukasa T, Nishizaki T. Regulation of AMPA receptor trafficking by O-glycosylation. Neurochem Res. 2010;35(5):782–8.

    CAS  PubMed  Google Scholar 

  • Kazemi Z, Chang H, Haserodt S, McKen C, Zachara NE. O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3beta-dependent manner. J Biol Chem. 2010;285(50):39096–107.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kearse KP, Hart GW. Lymphocyte activation induces rapid changes in nuclear and cytoplasmic glycoproteins. Proc Natl Acad Sci U S A. 1991;88(5):1701–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kelly WG, Dahmus ME, Hart GW. RNA polymerase II is a glycoprotein. Modification of the COOH-terminal domain by O-GlcNAc. J Biol Chem. 1993;268(14):10416–24.

    CAS  PubMed  Google Scholar 

  • Khidekel N, Ficarro SB, Clark PM, Bryan MC, Swaney LD, Rexach JE, et al. Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics. Nat Chem Biol. 2007;3(6):339–48.

    CAS  PubMed  Google Scholar 

  • Koffie RM, Hyman BT, Spires-Jones TL. Alzheimer’s disease: synapses gone cold. Mol Neurodegener. 2011;6(1):63.

    PubMed Central  PubMed  Google Scholar 

  • Kreppel LK, Hart GW. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J Biol Chem. 1999;274(45):32015–22.

    CAS  PubMed  Google Scholar 

  • Kreppel LK, Blomberg MA, Hart GW. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem. 1997;272(14):9308–15.

    CAS  PubMed  Google Scholar 

  • Lazarus MB, Nam Y, Jian J, Sliz P, Walker S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature. 2011;469(7331):564–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li X, Lu F, Wang JZ, Gong CX. Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting. Eur J Neurosci. 2006;23(8):2078–86.

    PubMed  Google Scholar 

  • Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002;3(3):175–90.

    CAS  PubMed  Google Scholar 

  • Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2004;101(29):10804–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Y, Li X, Yu Y, Shi J, Liang Z, Run X, et al. Developmental regulation of protein O-GlcNAcylation, O-GlcNAc transferase and O-GlcNAcase in mammalin brain. PLoS One. 2012;7(8):e43724.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lubas WA, Frank DW, Krause M, Hanover JA. O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J Biol Chem. 1997;272(14):9316–24.

    CAS  PubMed  Google Scholar 

  • Lyer SPN, Hart GW. Roles of the tetratricopeptide repeat domain in O-GlcNAc transferase targeting and protein substrate specificity. J Biol Chem. 2003;278(27):24608–16.

    Google Scholar 

  • Lyer SPN, Akimoto Y, Hart GW. Identification and cloning of a novel family of coiled-coil domain proteins that interact with O-GlcNAc transferase. J Biol Chem. 2003;278(7):5399–409.

    Google Scholar 

  • Lynch MA. Long-term potentiation and memory. Physiol Rev. 2004;84(1):87–136.

    CAS  PubMed  Google Scholar 

  • Macauley MS, Whitworth GE, Debowski AW, Chin D, Vocadlo DJ. O-GlcNAcase uses substrate-assisted catalysis: kinetic analysis and development of highly selective mechanism-inspired inhibitors. J Biol Chem. 2005;280(27):25313–22.

    CAS  PubMed  Google Scholar 

  • Marotta NP, Cherwien CA, Abeywardana T, Pratt MR. O-GlcNAc modification prevents peptide-dependent acceleration of α-synuclein aggregation. Chembiochem. 2012;13(18):2665–70.

    CAS  PubMed  Google Scholar 

  • Marz P, Stetefeld J, Bendfeldt K, Nitsch C. Reinstein, Shoeman RL et al. Ataxin-10 interacts with O-linked beta-N-acetylglucosamine transferase in the brain. J Biol Chem. 2006;281(29):20263–70.

    PubMed  Google Scholar 

  • Miller MW, Caracciolo MR, Berlin WK, Hanover JA. Phosphorylation and glycosylation of nucleoporins. Arch Biochem Biophys. 1999;367(1):51–60.

    CAS  PubMed  Google Scholar 

  • Muller U, Steinberger D, Nemeth AH. Clinical and molecular genetics of primary dystonias. Neurogenetics. 1998;1(3):165–77.

    CAS  PubMed  Google Scholar 

  • Nolte D, Muller U. Human O-GlcNAc transferase (OGT): genomic structure, analysis of splice variants, fine mapping in Xq13.1. Mamm Genome. 2002;13(1):62–4.

    CAS  PubMed  Google Scholar 

  • O'Donnell N, Zachara NE, Hart GW, Marth JD. Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol. 2004;24(2):1680–90.

    PubMed Central  PubMed  Google Scholar 

  • Ozcan S, Andrali SS, Cantrell JE. Modulation of transcription factor function by O-GlcNAc modification. Biochim Biophys Acta. 2010;1799(5–6):353–64.

    PubMed Central  PubMed  Google Scholar 

  • Ranuncolo SM, Ghosh S, Hanover JA, Hart GW, Lewis BA. Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J Biol Chem. 2012;287(28):23549–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ray MK, Datta B, Chakraborty A, Chattopadhyay A, Meza-Keuthen S, Gupta NK. The eukaryotic initiation factor 2-associated 67-kDa polypeptide (p67) plays a critical role in regulation of protein synthesis initiation in animal cells. Proc Natl Acad Sci U S A. 1992;89(2):539–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rexach JE, Rogers CJ, Yu SH, Tao J, Sun YE, Hsieh-Wilson LC. Quantification of O-glycosylation stoichiometry and dynamics using resolvable mass tags. Nat Chem Biol. 2010;6(9):645–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rexach JE, Clark PM, Mason DE, Neve RL, Peters EC, Hsieh-Wilson LC. Dynamic O-GlcNAc modification regulates CREB-mediated gene expression and memory formation. Nat Chem Biol. 2012;89(3):253–61.

    Google Scholar 

  • Roquemore EP, Chevrier MR, Cotter RJ, Hart GW. Dynamic O-GlcNAcylation of the small heat shock protein alpha B-crystallin. Biochemistry. 1996;35(11):3578–86.

    CAS  PubMed  Google Scholar 

  • Sakabe K, Wang Z, Hart GW. Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci U S A. 2010;107(46):19915–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sayat R, Leber B, Grubac V, Wiltshire L, Persad S. O-GlcNAc-glycosylation of beta-catenin regulates its nuclear localization and transcriptional activity. Exp Cell Res. 2008;314(15):2774–87.

    CAS  PubMed  Google Scholar 

  • Schirm M, Kalmokoff M, Aubry AP, Thibault P, Sandoz M, Logan SM. Flagellin from Listeria monocytogenes is glycosylated with beta-O-linked N-acetylglucosamine. J Bacteriol. 2004;186(20):6721–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol. 2010;120(2):131–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Selzer J, Hofmann F, Rex G, Wilm M, Mann M, Just I, Aktories K. Clostridium novyi alpha-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J Biol Chem. 1996;271(41):25173–7.

    CAS  PubMed  Google Scholar 

  • Shafi R, Lyer SPN, Ellies LG, O’Donnell N, Marek KW, Chui D, et al. The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci U S A. 2000;97(11):5735–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ. Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates. J Biol Chem. 2012;287(19):15395–408.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shepherd JD, Huganir RL. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol. 2007;23:613–43.

    CAS  PubMed  Google Scholar 

  • Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW. Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem. 2005;280(38):32944–56.

    CAS  PubMed  Google Scholar 

  • Slawson C, Lakshmanan T, Knapp S, Hart GW. A mitotic GlcNAcylation/phosphorylation signaling complex alters the posttranslational state of the cytoskeletal protein vimentin. Mol Biol Cell. 2008;19(10):4130–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Song M, Kim HS, Park JM, Kim SH, Kim IH, Ryu SH, et al. o-GlcNAc transferase is activated by CaMKIV-dependent phosphorylation under potassium chloride-induced depolarization in NG-108-15 cells. Cell Signal. 2008;20(1):94–104.

    CAS  PubMed  Google Scholar 

  • Tallent MK, Varghis N, Skorobogatko Y, Hernandez-Cuebas L, Whelan K, Vocadlo DJ, et al. In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation. J Biol Chem. 2009;284(1):174–81.

    CAS  PubMed  Google Scholar 

  • Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE. Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GlcNAcase and HAT activities. J Biol Chem. 2004;279(51):53665–73.

    CAS  PubMed  Google Scholar 

  • Toleman CA, Paterson AJ, Kudlow JE. The histone acetyltransferase NCOAT contains a zinc finger-like motif involved in substrate recognition. J Biol Chem. 2006;281(7):3918–25.

    CAS  PubMed  Google Scholar 

  • Torres CR, Hart GW. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem. 1984;259(5):3308–17.

    CAS  PubMed  Google Scholar 

  • Trinidad JC, Barkan DT, Gulledge BF, Thalhammer A, Sali A, Shoepfer R, et al. Global identification and characterization of both O-GlcNAcylation and phosphorylation at the murine synapse. Mol Cell Proteomics. 2012;11(8):215–29.

    PubMed Central  PubMed  Google Scholar 

  • Twine NA, Janitz K, Wilkins MR, Janitz M. Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer’s disease. PLoS One. 2011;6(1):e16266.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Verpelli C, Sala C. Molecular and synaptic defects in intellectual disability syndromes. Curr Opin Neurobiol. 2012;22(3):530–6.

    CAS  PubMed  Google Scholar 

  • Wang Z, Gucek M, Hart GW. Cross-talk between GlcNAcylation and phosphorylation: site-specific phosphorylation dynamics in response to globally elevated O-GlcNAc. Proc Natl Acad Sci U S A. 2008;105(37):13793–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Z, Udeshi ND, O’Malley M, Shabanowitz J, Hunt DF, Hart GW. Enrichment and site mapping of O-linked N-acetylglucosamine by a combination of chemical/enzymatic tagging, photochemical cleavage, and electron transfer dissociation mass spectrometry. Mol Cell Proteomics. 2010a;9(1):153–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Z, Namrata UD, Slawson C, Compton PD, Sakabe K, Cheung WD, et al. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci Signal. 2010b;3(104):ra2.

    PubMed Central  PubMed  Google Scholar 

  • Wang P, Lazarus BD, Forsythe ME, Love DC, Krause MW, Hanover JA. O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases. Proc Natl Acad Sci U S A. 2012;109(43):17669–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Webster DM, Teo CF, Sun Y, Wloga D, Gay S, Klonowski KD, et al. O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development. BMC Dev Biol. 2009;9:28.

    PubMed Central  PubMed  Google Scholar 

  • Whelan SA, Lane MD, Hart GW. Regulation of the O-linked beta-N-acetylglucosamine transferase by insulin signaling. J Biol Chem. 2008;283(31):21411–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Whelan SA, Dias WB, Thiruneelakantapillai L, Lane MD, Hart GW. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-Linked beta-N-acetylglucosamine in 3T3-L1 adipocytes. J Biol Chem. 2010;285(8):5204–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang X, Zhang F, Kudlow JE. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell. 2002;110(1):69–80.

    CAS  PubMed  Google Scholar 

  • Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451(7181):964–9.

    CAS  PubMed  Google Scholar 

  • Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, He Y, et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008;4(8):483–90.

    CAS  PubMed  Google Scholar 

  • Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8(4):393–9.

    CAS  PubMed  Google Scholar 

  • Zachara NE, O’Donnell N, Cheung WD, Mercer JJ, Marth JD, Hart GW. Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J Biol Chem. 2004;279(29):30133–42.

    CAS  PubMed  Google Scholar 

  • Zeidan Q, Wang Z, De Maio A, Hart GW. O-GlcNAc cycling enzymes associate with the translational machinery and modify core ribosomal proteins. Mol Biol Cell. 2010;21(12):1922–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang F, Su K, Yang X, Bowe DB, Paterson AJ, Kudlow JE. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell. 2003;115(6):715–25.

    CAS  PubMed  Google Scholar 

Download references

Conflicts of Interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD, 21205-2185, USA

    Olof Lagerlöf & Gerald W. Hart

Authors
  1. Olof Lagerlöf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerald W. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald W. Hart .

Editor information

Editors and Affiliations

  1. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA

    Robert K. Yu

  2. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, USA

    Cara-Lynne Schengrund

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lagerlöf, O., Hart, G.W. (2014). O-GlcNAcylation of Neuronal Proteins: Roles in Neuronal Functions and in Neurodegeneration. In: Yu, R., Schengrund, CL. (eds) Glycobiology of the Nervous System. Advances in Neurobiology, vol 9. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1154-7_16

Download citation

Publish with us

Policies and ethics

Search

Navigation