The potential role of tau protein O-glycosylation in Alzheimer's disease.

Single O-linked N-acetylglucosamine (O-GlcNAc) sugar residues can compete with phosphate groups to occupy specific sites on certain nuclear and cytosolic proteins. Here we show that inhibiting cellular kinase activities resulted in changes in protein O-glycosylation levels in heat-stable cytoskeletal protein fractions derived from primary neuronal cells. As increased phosphorylation of the microtubule-associated protein tau is one of the pathological hallmarks of Alzheimer's disease and glycosylation may play an influential role in this process. We observed a significant decrease in the protein O-GlcNAc glycosylation of a tau-enriched cytoskeletal fraction generated from AD post-mortem brain samples as compared with control, suggesting an inverse relationship between the two post-translational modifications. Finally, cells transfected with the cDNA coding for O-GlcNAc transferase (OGT) displayed altered tau phosphorylation patterns as compared with control cells, suggesting that changes in tau glycosylation may influence its phosphorylation state. The specificity of the changes in the phosphorylation of individual amino acid residues provides evidence for a targeted O-glycosylation of tau.

[1]  I. Grundke‐Iqbal,et al.  Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease , 2002, FEBS letters.

[2]  I. Grundke‐Iqbal,et al.  Glycosylation of microtubule–associated protein tau: An abnormal posttranslational modification in Alzheimer's disease , 1996, Nature Medicine.

[3]  A. Delacourte,et al.  Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins--a role in nuclear localization. , 2003, Biochimica et biophysica acta.

[4]  I. Grundke‐Iqbal,et al.  Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β , 2002, FEBS letters.

[5]  G. Hart,et al.  Cytoplasmic O-GlcNAc Modification of the Head Domain and the KSP Repeat Motif of the Neurofilament Protein Neurofilament-H* , 1996, The Journal of Biological Chemistry.

[6]  G. Hart,et al.  Glycosylation of mammalian neurofilaments. Localization of multiple O-linked N-acetylglucosamine moieties on neurofilament polypeptides L and M. , 1993, The Journal of biological chemistry.

[7]  Kazuyuki Takata,et al.  Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation In Vivo , 2003, Neuron.

[8]  D. Andrews,et al.  Cytoplasmic O‐glycosylation prevents cell surface transport of E‐cadherin during apoptosis , 2001, The EMBO journal.

[9]  I. Grundke‐Iqbal,et al.  Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5 , 2002, Neuroscience.

[10]  S. Fujita,et al.  Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse* , 2001, The Journal of Biological Chemistry.

[11]  D. Hanger,et al.  Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures , 1997 .

[12]  G. Hart,et al.  Dynamic nuclear and cytoplasmic glycosylation: enzymes of O-GlcNAc cycling. , 2003, Biochemistry.

[13]  C. Regan,et al.  Synaptosomal Sialyltransferase Glycosylates Surface Proteins that Are Inaccessible to the Action of Membrane‐Bound Sialidase , 1986, Journal of neurochemistry.

[14]  G. Hart,et al.  O-GlcNAc: a regulatory post-translational modification. , 2003, Biochemical and biophysical research communications.

[15]  P. Coleman,et al.  Reduction of O-Linked N-Acetylglucosamine-Modified Assembly Protein-3 in Alzheimer’s Disease , 1998, The Journal of Neuroscience.

[16]  G. Hart,et al.  Ogt-Dependent X-Chromosome-Linked Protein Glycosylation Is a Requisite Modification in Somatic Cell Function and Embryo Viability , 2004, Molecular and Cellular Biology.

[17]  Patrick R. Hof,et al.  Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 1 These authors contributed equally to this work. , 2000, Brain Research Reviews.

[18]  G. Hart,et al.  The Microtubule-associated Protein Tau Is Extensively Modified with O-linked N-acetylglucosamine* , 1996, The Journal of Biological Chemistry.

[19]  U. Wagner,et al.  Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly. , 1997, The Biochemical journal.

[20]  R. Cole,et al.  Localization of the O-GlcNAc transferase and O-GlcNAc-modified proteins in rat cerebellar cortex , 2003, Brain Research.

[21]  G. Hart,et al.  The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  B. Schmitz,et al.  O-linked N-acetylglucosamine levels in cerebellar neurons respond reciprocally to pertubations of phosphorylation. , 1999, European journal of biochemistry.

[23]  K. Breen,et al.  Overexpression of the α2,6 (N) sialyltransferase enzyme in human and rat neural cell lines is associated with increased expression of the polysialic acid epitope , 1999, Journal of neuroscience research.

[24]  B. Schmitz,et al.  O-linked N-acetylglucosamine is upregulated in Alzheimer brains. , 1995, Biochemical and biophysical research communications.

[25]  G. Hart,et al.  Regulation of a Cytosolic and Nuclear O-GlcNAc Transferase , 1999, The Journal of Biological Chemistry.

[26]  R. Cole,et al.  Cytosolic O‐glycosylation is abundant in nerve terminals , 2001, Journal of neurochemistry.