Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5

  title={Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5},
  author={F. Liu and Tanweer M. Zaidi and Khalid Iqbal and Inge Grundke‐Iqbal and Cheng-Xin Gong},

O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease.

It is demonstrated that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide beta-N-acetylglucosamine (Glc NAc) attaches to serine/threonine residues via an O-linked glycosidic bond, which reveals a mechanism of regulation of tau phosphorylation.

Dephosphorylation of Tau by Protein Phosphatase 5

The kinetics of dephosphoryation of phospho-tau by PP5 were investigated and found that PP5 had a Km of 8–13 μm toward tau, which is similar to that of PP2A, the major known tau phosphatase.

Dephosphorylation of microtubule‐associated protein tau by protein phosphatase 5

The results suggest that PP5 plays a role in the dephosphorylation of tau and might be involved in the molecular pathogenesis of Alzheimer's disease.

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

It is shown that inhibiting cellular kinase activities resulted in changes in protein O-glycosylation levels in heat-stable cytoskeletal protein fractions derived from primary neuronal cells, suggesting an inverse relationship between the two post-translational modifications.

Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer's disease.

The results indicate that truncation of PP2B by calpain I elevates its activity but does not counteract the abnormal hyperphosphorylation tau in AD brain.

Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration.

Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylations of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia.

Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation

PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain, partially due to a downregulation of PP2A activity in AD brain.

Anesthesia induces phosphorylation of tau.

It is found that anesthesia for short periods induced tau phosphorylation at Thr181, Ser199, Thr205, Thr212, Ser262, and Ser404 to small, but significant, extents, which appeared to result from anesthesia-induced activation of stress-activated protein kinases.



Glycosylation of microtubule–associated protein tau: An abnormal posttranslational modification in Alzheimer's disease

Although the abnormal phosphorylation might promote aggregation of tau and inhibition of the assembly of microtubules, glycosylation appears to be responsible for the maintenance of the PHF structure.

Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

It is suggested that protein phosphatase 2A participates in regulation of tau phosphorylation, processing, and function in vivo and can lead to Alzheimer-like abnormal hyperphosphorylated tau.

Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation.

It is shown that the AT100 epitope is generated by a complex sequence of sequential phosphorylation, first of Ser199, Ser202 and Thr205 (around the epitope of antibody AT8), next of Thr212 by glycogen synthase kinase (GSK)-3beta (a proline-directed kinase), then of Ser214 by protein kinase A (PKA).

Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356.

Evidence is presented that phosphorylation of both these sites occurs in cultured nerve cells under certain conditions, indicating their potential physiological relevance.

Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease.

It is suggested that the abnormal phosphorylation of tau might be responsible for the breakdown of microtubules in affected neurons in AD not only because the altered protein has little microtubule-promoting activity but also because it interacts with normal tau, making the latter unavailable for promoting the assembly of tubulin intomicrotubules.

Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein.

It is suggested that lack of amino-terminal inserts and extra microtubule binding domain repeat in fetal human brain might be protective from Alzheimer's neurofibrillary degeneration, and that hyperphosphorylation of tau appears to be sufficient to acquire AD P-tau characteristics.

cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease

It is demonstrated that CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer’s disease, but not in normal brain tissue, and that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau.