Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) among the Chamorros in Guam is remarkably high. The patients with ALS have clinical and pathological characteristics similar to those in other parts of the world. The PDC patients display parkinsonism and progressive dementia and show a characteristic neuronal loss in certain parts of the central nervous system such as the hippocampus and substantia nigra. The Guamanian patients with ALS and PDC commonly have widespread Alzheimer's neurofibrillary changes, but without the associated senile plaques. We have applied immunohistochemical procedures to examine the expression of marker substances in Guamanian ALS and PDC. The markers studied include tau protein, ubiquitin, beta proteins, synaptophysin, calcineurin, Met-enkephalin, substance P and tyrosine hydroxylase. The results were compared with the findings in patients with Alzheimer's disease, Parkinson's disease, sporadic ALS and familial ALS.
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PMID:Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam: immunohistochemical studies. 158 17

We consider the interactions of tau protein with microtubules from two points of view, phosphorylation and domain structure. Tau can be phosphorylated at many sites and by several kinases, notably by proline-directed kinases (MAPK, GSK-3, cdk5) which generate Alzheimer-like antibody epitopes. Other kinases phosphorylate Ser 262, a site that has a particularly pronounced influence on the affinity of tau for microtubules. All of these sites can be cleared by phosphatases PP-2a and calcineurin. The site Ser262 lies within the repeat domain of tau. However, when probing the domains of tau for their effects on microtubule binding, nucleation, assembly, or bundling, the repeat domain has only a weak influence. Whereas the repeat domain of tau binds to microtubules with low affinity, repeat-less tau binds strongly yet unproductively in terms of microtubule assembly. Productive binding of tau to microtubules depends on the combination of (some) repeats with the flanking regions, as if the flanking regions acted as "jaws" for the proper positioning of tau on the microtubule surface.
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PMID:Tau domains, phosphorylation, and interactions with microtubules. 756 45

The accumulation of hyperphosphorylated tau species in neurons in Alzheimer's disease (AD) might result from a relative decrease in their content of protein phosphatases. In this study we have investigated the immunocytochemical distribution of calcineurin (phosphatase 2B) in the hippocampus and temporal cortex of human control subjects and in AD. Calcineurin was strongly expressed in neuronal perikarya and dendrites but only weakly in white matter tracts, both in controls and in AD. The distribution of calcineurin was preserved in AD. By double-immunolabelling with calcineurin antibodies and the AT8 antibody to paired helical filament-tau, it was observed that a strong calcineurin immunoreactivity was still present in many neurons containing neurofibrillary tangles (NFT). Calcineurin was present in dystrophic neurites in some senile plaques (SP) located in the hippocampal formation but more rarely in neocortical areas; this calcineurin immunoreactivity did not always overlap with the tau immunoreactivity in SP. These results suggest that development of NFT in most neurons does not result from a major decrease of calcineurin expression.
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PMID:Calcineurin (phosphatase 2B) is present in neurons containing neurofibrillary tangles and in a subset of senile plaques in Alzheimer's disease. 760 Jan 82

We identified two major substrates for the proline-directed protein kinases--cdc2 kinase and tau protein kinase II (TPKII)--in the cytosol fraction from rat brains. The molecular masses of the proteins were 80 and 46 kDa. Because the 80-kDa protein was phosphorylated by protein kinase C and was heat stable, we examined the possibility that the protein might be myristoylated alanine-rich C kinase substrate (MARCKS). On the basis of a comparison between the properties of the 80-kDa protein and purified MARCKS, we concluded that the 80-kDa protein is indeed MARCKS. The amounts of phosphate incorporated into MARCKS by protein kinase C, cdc2 kinase, and TPKII were 1.7, 1.4, and 0.6 mol/mol of the protein, respectively. Two-dimensional tryptic peptide mapping indicated that phosphorylation sites by protein kinase C and proline-directed protein kinases completely differed. Only the seryl residue was phosphorylated by protein kinase C, whereas both seryl and threonyl residues were phosphorylated by cdc2 kinase and TPKII. Phosphorylation of MARCKS by protein kinase C inhibited the binding to calmodulin, whereas phosphorylation by cdc2 kinase and TPKII significantly increased the binding to calmodulin. The holoenzyme of protein phosphatase 2A dephosphorylated MARCKS that had been phosphorylated by protein kinase C, cdc2 kinase, or TPKII, whereas calcineurin was unable to dephosphorylate it. These results suggest that cdc2 kinase and TPKII regulate the functions of MARCKS in different ways from protein kinase C.
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PMID:Phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) by proline-directed protein kinases and its dephosphorylation. 761 38

Alterations in situ in the phosphorylation state of the microtubule-associated protein tau were examined in response to increasing intracellular levels of Ca2+ through N-methyl-D-aspartate (NMDA)-receptor activation, or activating cyclic AMP (cAMP)-dependent protein kinase (cAMP-PK), in rat cerebral-cortical slices. Increasing intracellular concentrations of Ca2+ by treatment of the brain slices with the glutamate analogue NMDA in depolarizing conditions (55 mM KCl) resulted in dephosphorylation of tau. Addition of KCl+NMDA to the slices resulted in a 40% decrease in 32P incorporation into tau, whereas addition of KCl or NMDA alone had no effect on tau phosphorylation. The KCl+NMDA-induced dephosphorylation of tau was blocked by the non-competitive NMDA-receptor antagonist MK801. Determine the involvement of the Ca2+/calmodulin-dependent phosphatase, calcineurin, in the KCl+NMDA-induced dephosphorylation of tau, slices were pretreated with the calcineurin inhibitor Cyclosporin A. Pretreatment of the rat brain slices with Cyclosporin A completely abolished the dephosphorylation of tau induced by the addition of KCl+NMDA. The dephosphorylation of tau in situ was site-selective, as indicated by the loss of 32P label from only a few select peptides. Activation of cAMP-PK by stimulating adenylate cyclase in rat cerebral-cortical slices with forskolin resulted in a 73% increase over control levels in 32P incorporation into immunoprecipitated tau. Two-dimensional phosphopeptide mapping revealed that most of the sites on tau phosphorylated in brain slices in response to increased cAMP levels were the same as those phosphorylated on isolated tau by purified cAMP-PK. Although the state of tau phosphorylation is certainly regulated by many protein phosphatases and kinases in vivo, to our knowledge this study provides the first direct evidence of a specific protein phosphatase and kinase that modulate the phosphorylation state of tau in situ.
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PMID:Modulation of the phosphorylation state of tau in situ: the roles of calcium and cyclic AMP. 761 80

The abnormally phosphorylated forms of tau factor are major constituents of neurofibrillary tangles in Alzheimer's disease brain. In order to investigate protein phosphatases which are related to dephosphorylation of abnormal phosphorylation sites, we examined the dephosphorylation of tau factor phosphorylated by three proline-directed type protein kinases. Tau factor phosphorylated by cdc2 kinase and tau protein kinase II was dephosphorylated by the holoenzyme of protein phosphatase 2A and calcineurin, while either the catalytic subunit of protein phosphatase 2A or protein phosphatase 2C could not catalyze the dephosphorylation. From the kinetic analysis, we concluded that tau factors phosphorylated by the protein kinases serve as good substrates for protein phosphatase 2A and calcineurin. On the other hand, tau factor phosphorylated by glycogen synthase kinase 3 alpha was dephosphorylated by the catalytic subunit of protein phosphatases 2A as well as the holoenzyme of protein phosphatase 2A and calcineurin. It has been reported that serines 199, 202 and 396 according to the numbering of the longest human tau isoform are among the major abnormal phosphorylation sites of tau factor. We synthesized two phosphopeptides which contained phosphoserines 199 and 202 or phosphoserine 396 and prepared the polyclonal antibodies specific for the phosphopeptides. Using these antibodies, we confirmed that the holoenzyme of protein phosphatase 2A and calcineurin could dephosphorylate phosphoserines 199, 202 and 396 in tau factor. The catalytic subunit of protein phosphatase 2A could dephosphorylate phosphoserine 396 but not phosphoserines 199 and 202. Neurofibrillary tangles in Alzheimer's disease brain were immunostained with both antibodies but the normal neurons in the normal aged brains were not. The results suggest that protein phosphatase 2A and calcineurin can be involved in the dephosphorylation of abnormal phosphorylation sites in tau factor and that the dephosphorylation of phosphoserine 396 is differently regulated from phosphoserines 199 and 202.
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PMID:Dephosphorylation of abnormal sites of tau factor by protein phosphatases and its implication for Alzheimer's disease. 778 67

Calcineurin is a calmodulin-dependent serine-threonine phosphatase found in many cell types but most abundant in neurons. To determine its localization in developing neurons, dissociated cultures from embryonic day 15 rat cerebellum were analyzed immunocytochemically after treatment with cytoskeletal-disrupting drugs. During the initial outgrowth of neurites, calcineurin is enriched in growth cones where its localization depends upon the integrity of both microtubules and actin filaments. Treatment with cytochalasin shifts calcineurin from the growth cone to the neurite shaft, and with nocadozole calcineurin translocates to the cell body. Therefore calcineurin is well positioned to mediate interactions between cytoskeletal systems during neurite elongation. By 14 d in culture, when the neurons have developed extensive neuronal contacts and synapses are present, calcineurin is predominantly in the neurite shaft. Incubation of cultured cells with Cyclosporin A or a specific peptide, both of which selectively inhibit calcineurin's phosphatase activity, prevented axonal elongation. Because the microtubule-associated protein tau appears to play a key role in asymmetric neurite elongation, we examined modifications in its phosphorylation state resulting from calcineurin inhibition. In contrast to the normal development of cerebellar macroneurons in which reactivity with the phosphorylation-dependent antibody, tau-1, progressively increases, there was a persistent inhibition of tau-1 reactivity in cells exposed to Cyclosporin A. These findings suggest a role for calcineurin in regulating tau phosphorylation and possibly modulating other steps required for the determination of polarity.
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PMID:Calcineurin is associated with the cytoskeleton of cultured neurons and has a role in the acquisition of polarity. 816 6

We have shown previously that brain tissue contains protein kinases which can phosphorylate tau protein to a state reminiscent of the pathological state of Alzheimer paired helical filaments (PHFs); these include proline-directed kinases which phosphorylate SP or TP motifs (such as MAP kinase and GSK-3) [Drewes et al. (1992); Mandelkow et al. (1992)], as well as a novel kinase which phosphorylates S262 of tau protein and thereby strongly reduces the binding of tau to microtubules [Biernat et al. (1993)]. Here we report on the corresponding phosphatases in brain which normally keep the 'pathological' sites free of phosphate. The major phosphatases acting on tau are calcineurin and PP-2A, but not PP-1. Both are present and active in brain extracts, they can dephosphorylate recombinant tau after prior phosphorylation with either MAP kinase, GSK-3, or brain extract, and the course of dephosphorylation can be monitored with antibodies diagnostic of the pathological state of tau. Both phosphatases also act directly on PHF tau isolated from Alzheimer brains.
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PMID:Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. 828 5

Hyperphosphorylated forms of the microtubule-associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz-50, 5E2, and Tau-1. The results indicate that tau phosphorylation was altered in a dose-dependent manner by the phosphatase inhibitor okadaic acid, but not by N-methyl-D-aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed "PHF-like tau," produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF-like tau peptides was blocked by KN-62, 1[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, an inhibitor of Ca2+/calmodulin-dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF-like tau. These data suggest that phosphorylation of tau is regulated by Ca(2+)-dependent protein kinases and okadaic acid-sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer's disease.
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PMID:Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. 849 35

We have reported that many sites of tau in fetal brain (fetal-tau) as well as in paired helical filaments (PHF-tau) are phosphorylated. In the present study, we used site-specific antibodies and peptide mapping to examine protein phosphatases involved in dephosphorylation of fetal-tau and PHF-tau. Immunoblot analysis and electrophoretic mobility showed that protein phosphatases 1 and 2A and calcineurin could dephosphorylate fetal-tau and PHF-tau. Phosphoserines 199, 202, 396, and 413 and phosphothreonine 231, numbered according to the longest human tau isoform, were dephosphorylated, as shown by the immunoblot analysis. Phosphoserine 422 was dephosphorylated by protein phosphatase 2A and calcineurin, but not by protein phosphatase 1. Peptide mapping with Achromobacter lyticus protease 1 showed that phosphoserines 199, 202, 235, and 396 and phosphothreonine 231 were dephosphorylated by protein phosphatases. Fetal-tau was more rapidly dephosphorylated by protein phosphatase 2A and calcineurin than PHF-tau. Interestingly, PHF-tau which had not been solubilized with guanidine HCl was little dephosphorylated by protein phosphatases. Thus, PHF-tau in neurofibrillary tangles of Alzheimer's disease brain is likely to be resistant to dephosphorylation by protein phosphatases.
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PMID:Dephosphorylation of fetal-tau and paired helical filaments-tau by protein phosphatases 1 and 2A and calcineurin. 872 Jan 39


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