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 microtubule-associated protein tau plays an important role in the dynamics of microtubule assembly necessary for axonal growth and neurite plasticity. Ischemia disrupts the neuronal cytoskeleton both by promoting proteolysis of its components and by affecting kinase and phosphatase activities that alter its assembly. In this study the effect of ischemia and reperfusion on the expression and phosphorylation of tau was examined in a reversible model of spinal cord ischemia in rabbits. tau was found to be dephosphorylated in response to ischemia with a time course that closely matched the production of permanent paraplegia. Dephosphorylation of tau was limited to the caudal lumbar spinal cord. In a similar manner, Ca2+/calmodulin-dependent kinase II activity was reduced only in the ischemic region. Thus, dephosphorylation of tau is an early marker of ischemia as is the rapid loss of Ca2+/calmodulin-dependent kinase II activity. tau, however, was rephosphorylated rapidly during reperfusion at site(s) that cause a reduction in its electrophoretic mobility regardless of the neurological outcome. Alterations in phosphorylation or degradation of tau may affect microtubule stability, possibly contributing to disruption of axonal transport but also facilitating neurite plasticity in a regenerative response.
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PMID:Changes in phosphorylation of tau during ischemia and reperfusion in the rabbit spinal cord. 852 66

The mechanism of dephosphorylation of multiphosphorylated proteins in the brain is not well understood. We have used the multiphosphorylated protein, phosvitin as a model substrate and undertaken the purification and characterization of brain phosphatases that preferentially dephosphorylate multiphosphorylated proteins. Two phosvitin phosphatase activities, termed Phosvitin Phosphatase 1 and 2 (PvP1, PvP2), which show acidic pH optima were resolved from the 33,000g supernatant fraction from rat brain by a procedure employing successive DEAE-cellulose, Sepharose 6B, second DEAE-cellulose and FPLC/Superose 6 chromatography steps. Following FPLC/Superose 6 size exclusion chromatography of PvP1 and PvP2, single peaks of phosvitin phosphatase activities were eluted in the range of 160-220 kDa with acidic pH optima. When FPLC/Sepharose 6 chromatography was performed in the presence of 0.5 M NaCl and 0.1% Triton X-100, low molecular mass protein phosphatase forms were produced in addition to the high-M, activity peak, ranging from 25 to 35 kDa (PvP1) and from 15 to 25 kDa (PvP2). Under these conditions, both high- and low-M, forms of PvP1 and PvP2 exhibited neutral pH optima. Both phosphatases dephosphorylate also (i) phosphorylase a, (ii) the alpha and beta subunits of phosphorylase kinase, and (iii) the microtubule-associated protein tau, phosphorylated by cAMP-dependent protein kinase. The present results suggest that two forms of protein phosphatases, displayed molecular and biochemical characteristics both similar and distinct from type 1 and type 2A protein phosphatases, are present in rat brain.
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PMID:Partial purification and characterization of two phosvitin phosphatases from rat brain. 862 49

The microtubule-associated protein tau is more highly phosphorylated at certain residues in developing brain and in Alzheimer's disease paired helical filaments than in adult brain. We examined the regulation of tau phosphorylation at some of these sites in rat brain using the phosphorylation state-dependent anti-tau antibodies AT8, Tau1, and PHF1. The AT8 and PHF1 antibodies bind to phosphorylated tau, while Tau1 binds to unphosphorylated tau. Levels of tau reactive for AT8 were high only during the first postnatal week, with levels in adult declining to approximately 5% of the levels in neonates. In neonatal forebrain slices, tau became rapidly dephosphorylated at the AT8 and Tau1 sites during incubation at 34 degrees C, but was incompletely dephosphorylated at the PHF1 site. Dephosphorylation at AT8 sites, but not at Tau1 or PHF1 sites, was completely inhibited by 1 microM okadaic acid. Hence the regulation of tau phosphorylation by okadaic acid-sensitive phosphatase(s) was site-specific. Addition of 1 microM okadaic acid after dephosphorylation at the AT8 locus yielded a partial recovery of AT8 immunoreactivity, and incubation with basic fibroblast growth factor increased phosphorylation at the AT8 site in a dose-dependent manner. These results indicate that endogenously active and basic fibroblast growth factor stimulated tau kinases directed toward an Alzheimer's disease-related site were present in the slices. In adult brain slices, the small pool of AT8-reactive tau was remarkably insensitive to dephosphorylation during incubation, and okadaic acid treatment induced only small increases in AT8 immunoreactivity. These results suggest that tau phosphorylation in adult brain is less dynamic than in neonatal brain. These findings indicate that neonatal tau is not only phosphorylated more highly than adult tau, but also more dynamically regulated by protein phosphatases and protein kinases than adult tau. The inability of okadaic acid to induce large increases in tau phosphorylation in adult rat brain slices suggests that a loss of protein phosphatase activity alone would not be sufficient to produce the hyperphosphorylation observed in Alzheimer's disease paired helical filaments. Stimulation of kinase activity by basic fibroblast growth factor is likely to modulate tau function during development, and may contribute to the genesis of hyperphosphorylated tau in Alzheimer's disease.
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PMID:Site-specific regulation of Alzheimer-like tau phosphorylation in living neurons. 873 Jul 15

Pyramidal neurons in affected regions of Alzheimer's disease (AD) brain contain neurofibrillary tangles (NFT), aggregates of paired helical filaments (PHF) composed mainly of phosphorylated microtubule-associated protein tau. To explore the role of tau phosphorylation in the aggregation of tau into PHF, we constructed mammalian cell culture systems producing high levels of intracellular phosphorylated tau. COS-1 fibroblast-like cells were transiently transfected to simultaneously express tau, MAP kinase (MAPK), and MAP kinase kinase (MAPKK), or alternatively to express tau and glycogen synthase kinase 3 (GSK3). B103 neuron-like cells (which contain MAPK but little tau or GSK3) were stably transfected to express tau or tau and GSK3. In both systems, GSK3-transfected cells contained tau AT8/M (defined by AT8 staining and tau PHF-like mobility), but MAPK-transfected cells required phosphatase inhibitors, such as okadaic acid (OKA) or calyculin (CAL), to produce tau AT8/M. In vitro, the same concentrations of CAL and OKA inhibit phosphatases 1 and 2A (PP1 and PP2A), except that 100-1000 times as much OKA is needed to inhibit PP1. Inducing tau phosphorylation at the AT8 site in MAPK-transfected cells required 2-10 times more OKA than CAL, suggesting both PP1 and PP2A helped block the phosphorylation. Though levels of tau AT8/M reached 2-8% of total cellular proteins in COS-1 cells, the ratio of particulate to supernatant tau levels did not increase, and no tangles were observed; perhaps post-translational modifications or co-aggregating proteins are needed to induce PHF.
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PMID:Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement. 875 Aug 56

Based on video-enhanced differential interference contrast (DIC) microscopy, we developed a small-scale method which is capable of measuring both the lengths and the number densities of microtubules (MTs) assembled in vitro. With this method, effect of dephosphorylation on the activity of bovine brain tau protein to promote the assembly of tubulin at physiological concentration (15 microM) was quantitatively analyzed. The MT number density was selectively reduced when tau isolated directly in the presence of phosphatase inhibitors (N-tau) was dephosphorylated in vitro (DP-tau), without significant changes in the mean MT length or the binding affinity toward preformed MTs. Tau obtained from brain MTs (MT-tau) also exhibited lower nucleation activity in spite of its high MT-binding affinity. The results indicate that nucleation, elongation and MT-binding are distinct aspects of tau function which are differentially affected by the phosphorylation state of tau.
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PMID:Reduced microtubule-nucleation activity of tau after dephosphorylation. 875 84

Neurofibrillary tangles (NFT), neuritic plaques, and dystrophic neurites are the classic neuropathologic hallmarks of Alzheimer's disease (AD), all of which contain to varying degrees abnormally and/or hyperphosphorylated forms of the microtubule-associated protein tau. Protein phosphatase 2B (calcineurin) dephosphorylates tau isolated from AD brains to control levels in vitro as well as regulates tau phosphorylation and function in vivo. It has been hypothesized that the changes in tau phosphorylation observed in AD may be due to increases in kinase activity and/or decreases in phosphatase activity. In order to investigate the latter possibility, we examined calcineurin enzyme activity using the substrate para-nitrophenyl-phosphate (pNPP) in postmortem brain samples from individuals with moderate to severe AD (n = 8) and age-matched controls (n = 7). The stimulation of calcineurin activity by manganese chloride (1 mM) was reduced by 60% (p < 0.01) in whole-cell homogenates prepared from AD temporal cortex (Brodmann area 38). On the other hand, in P2 membrane fractions, the stimulation of calcineurin activity by manganese chloride as well as nickel chloride (1 mM) was reduced by 37% (p < 0.05) and 79% (p < 0.01), respectively. The manganese-stimulated calcineurin activity in the temporal cortex inversely correlated with both the number of NFT (r = -0.60, p < 0.02) and neuritic/core plaques (r = -0.63, p < 0.02) in whole-cell homogenates, but only with NFT (r = -0.61, p < 0.02) in P2 membrane fractions. The nickel-stimulated calcineurin activity did not correlate with neuropathology measures in either whole-cell or P2 membrane fractions. In striate visual cortex (Brodmann area 17), an area relatively unaffected in AD, neither whole-cell nor P2 membrane calcineurin activity were significantly altered. To our knowledge, this is the first report of a reduction in calcineurin phosphatase activity in AD which correlates with the neuropathological features in a region-, subcellular fraction-, and divalent cation-specific manner.
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PMID:Reduction of calcineurin enzymatic activity in Alzheimer's disease: correlation with neuropathologic changes. 875 82

Mechanisms underlying axonogenesis remain obscure. Although a large number of proteins eventually become polarized to the axonal domain, in no case does protein compartmentalization occur before or simultaneous with the earliest morphological expression of axonal properties. How then might initially unpolarized proteins, such as the microtubule-associated protein tau, play a role in the microdifferentiation of axons? We hypothesized that tau function could be locally regulated by phosphorylation during the period of axonogenesis. To test this hypothesis, we mapped relative levels of tau phosphorylation within developing cultured hippocampal neurons. This was accomplished using calibrated immunofluorescence ratio measurements employing phosphorylation state-dependent and state-independent antibodies. Tau in the nascent axon is more highly dephosphorylated at the site recognized by the tau-1 antibody than tau in the somatodendritic compartment. The change in phosphorylation state from soma to axon takes the form of a smooth proximo-distal gradient, with tau in the soma, immature dendrites and proximal axon approximately 80% phosphorylated at the tau-1 site, and that in the axonal growth cone only 20% phosphorylated. The existence of real spatial differences in tau phosphorylation state was confirmed by in situ phosphatase and kinase treatment. Pervanadate, a tyrosine phosphatase inhibitor, induced rapid tau dephosphorylation within live cells, effectively abolishing the phosphorylation gradient. Thus, the gradient is dynamic and potentially regulatable by upstream signals involving tyrosine phosphorylation. Phosphorylation gradients are likely to be present on many neuronal proteins in addition to tau, and their modulation by transmembrane signals could direct the establishment of polarity.
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PMID:A spatial gradient of tau protein phosphorylation in nascent axons. 879 28

Phosphorylation of the microtubule-associated protein tau regulates its binding to microtubules; highly phosphorylated tau is also a prime component of paired helical filaments (PHFs) of Alzheimer's disease (AD). Tau from freshly biopsied human, monkey, and rat brain share similar electrophoretic mobility patterns and overlapping phosphorylated epitopes when compared to AD tau isolated from AD brain. We compared the microtubule reassembly competence of fresh isolates of phosphorylated tau to that of maximally dephosphorylated tau and tau from AD brain. A rapid procedure was developed which permitted the enrichment of phosphorylated and dephosphorylated tau from human biopsies in the absence of protein kinase and phosphatase activity. Microtubule assembly assays, using a spectrophotometric measure and purified bovine brain tubulin, were used to correlate assembly competence with states of tau electrophoretic mobility. Maximally dephosphorylated human biopsy-derived tau and monkey tau were assembly competent; tau from AD brain was virtually unable to direct microtubule assembly. Unmodified, biopsy-derived tau from non-AD brain was intermediate in assembly competence relative to AD tau and dephosphorylated tau. Several lines of evidence were used to correlate phosphorylation states of tau with microtubule assembly. First, in vitro dephosphorylation of human biopsy-derived tau with either PP2A or PP2B alone or in combination led to increasing assembly competence as the electrophoretic mobility of tau increased. Second, addition of the protein phosphatase inhibitor okadaic acid (10 microM) to brain-slice preparations slowed electrophoretic mobility of tau and decreased binding competence. We suggest that tau derived from freshly-biopsied brain exists in a range of phosphorylated states, and that dephosphorylation by PP2A and/or PP2B increases microtubule assembly competence.
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PMID:Microtubule assembly competence analysis of freshly-biopsied human tau, dephosphorylated tau, and Alzheimer tau. 892 25

Protein phosphatase inhibitors, okadaic acid and Caliculin A, were used to investigate how perturbation of phosphorylation and dephosphorylation processes might affect neurite and synapse structure in cultures of fetal rat hippocampal neurons. Drug treatments induced neuritic tree modification, with retraction of the processes and the appearance of dilatations along the neurites. The characteristic dotlike pattern of immunoreactivity of synaptic vesicle proteins disappeared. Normal synapses were extremely rare by ultrastructural observation. Vesicles of various diameters accumulated in the dilatations, as did organelles and amorphous material, suggesting impaired axonal transport. Hyperphosphorylation of tau protein was also observed as indicated by the shift in the electrophoretic mobility of a 32P-labeled 55-kDa band and by immunoblot with epitope-specific tau antibody. Our results show that inhibition of protein phosphatases 1 and 2A results in a modification of the neuritic tree structure, with loss of neuronal processes, phosphorylation of a tau isoform, and a decrease in the number of synapses. These neuronal features are present in Alzheimer's disease (AD). Our results suggest that the two events might be related and provide a potential link between the biochemical hallmark of AD (hyperphosphorylation of tau) and a pathological finding of primary clinical relevance (the synaptic loss).
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PMID:Protein phosphatase inhibitors induce modification of synapse structure and tau hyperphosphorylation in cultured rat hippocampal neurons. 918 66

The objective of this study was to asses the response of the microtubule-associated protein tau to acute rise in the concentration of free cytoplasmic calcium ([Ca2+]i) in rat cortical neurons and mouse cerebellar granule cells in culture. One-hour exposure to glutamate (100 microM), N-methyl-D-aspartate (100 microM), KCl (50 mM), and ionomycin (5 microM) led to tau protein dephosphorylation as indicated by an appearance of additional faster moving bands on Western immunoblots with a phosphorylation-independent antibody and an increase in the tau-1 immunoreactivity associated with the appearance of an additional faster moving band. Lowering the extracellular concentration of Ca2+ to less than 1 microM fully prevented the drug-induced tau protein dephosphorylation indicating a dependence on Ca2+ influx from the extracellular environment. Administration of okadaic acid (inhibitor of phosphatase 1/2A) simultaneously with the above mentioned drugs decreased the drug-mediated dephosphorylation. Pre-incubation with okadaic acid fully prevented the dephosphorylation. Treatment with cypermethrin (inhibitor of phosphatase 2B) was without effect when administered either alone, simultaneously with the drugs, or pre-incubated. These findings indicate that, independently of the influx pathway, [Ca2+]i elevation leads to dephosphorylation of the microtubule-associated protein tau and implicate phosphatase 1 and/or 2A in the process.
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PMID:Acute rise in the concentration of free cytoplasmic calcium leads to dephosphorylation of the microtubule-associated protein tau. 920 May 3


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