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)

Microtubule-associated protein tau is known to be hyperphosphorylated in Alzheimer disease brain and this abnormal hyperphosphorylation is associated with an inability of tau to promote the assembly of microtubule in the affected neurons. Our previous studies demonstrated that abnormally phosphorylated tau could be dephosphorylated after treatment with alkaline phosphatase, thereby suggesting that the abnormal phosphorylation of tau might in part be the result of a deficiency of the phosphoprotein phosphatase system in patients with Alzheimer disease. In the present study we used 32P-labeled phosphorylase kinase and poly(Glu, Tyr) 4:1 as substrates to measure phosphoprotein phosphatase activities in Alzheimer disease and control brains. The activities of phosphoseryl/phosphothreonyl-protein phosphatase types 1, 2A, 2B, and 2C and of phosphotyrosyl-protein phosphatase in frontal gray and white matters from 13 Alzheimer brains were determined and compared with those from 12 age-matched control brains. The activities of type 1 phosphatase and phosphotyrosyl phosphatase in gray matter and of type 2A phosphatase in both gray and white matters were significantly lower in Alzheimer disease brains than in controls. These findings suggest that the hyperphosphorylation of tau in Alzheimer disease brain could result from a protein dephosphorylation defect in vivo. The decrease in the phosphatase activities in Alzheimer disease might also be involved in the formation of beta-amyloid by augmenting the amyloidogenic pathway processing of beta-amyloid precursor protein.
J Neurochem 1993 Sep
PMID:Phosphoprotein phosphatase activities in Alzheimer disease brain. 839 66

The entry of Theileria parva sporozoites into bovine lymphocytes occurs rapidly and involves a defined series of events. In the present study the role of calcium in sporozoite entry was examined. Depletion of Ca2+ from the external medium had little effect on sporozoite entry suggesting that the initial sporozoite-host cell interaction is a Ca(2+)-independent process. Sporozoite entry could, however, be inhibited by a range of Ca2+ channel blockers (verapamil, nicardipine, diltiazem) and calmodulin antagonists (TPF, chloropromazine, W7 and calmidazolium). Evidence is also presented that demonstrates that sporozoite entry is dependent on changes in sporozoite cytosolic Ca2+ caused by the release of Ca2+ from intrasporozoite stores. First, reagents that produced an influx of Ca2+ into the parasite (A23187) blocked entry. Second, depletion of intrasporozoite Ca2+ levels (10 microM A23187 + 1.0 mM EGTA) or an increase in the cytoplasmic buffering capacity of the sporozoite cytoplasm (by preloading sporozoites with MAPT/AM) inhibited invasion. Third, sporozoite entry was inhibited by TMB-8 which blocks the release of Ca2+ from intracellular stores. Lastly, treatment of sporozoites with the Ca(2+)-mobilizing agents thapsigargin, cyclopiazonic acid but not InsP3 prevented sporozoite entry. In these cases the premature release of intrasporozoite Ca2+ inhibited sporozoite binding to the host cell surface; sporozoites that bound became internalized at rates comparable to the controls. In contrast, treatment of lymphocytes with these reagents had no significant effect on sporozoite entry. Collectively these results demonstrate that the mobilization of Ca2+ from intrasporozoite stores following sporozoite binding to the host cell surface is essential for successful parasite invasion.
Eur J Cell Biol 1995 Sep
PMID:Mobilization of intrasporozoite Ca2+ is essential for Theileria parva sporozoite invasion of bovine lymphocytes. 854 93

Hyperphosphorylated tau protein is the major constituent of the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions of Alzheimer's disease (AD). Hyperphosphorylation of tau is believed to be the critical event that leads to filament assembly. Identification of the responsible protein kinases is therefore a key step towards an understanding of the pathogenesis of AD. Mitogen-activated protein kinase, glycogen synthase kinase-3 (GSK3) and neuronal cdc2-like kinase have been shown to phosphorylate tau protein in vitro at a number of sites that are phosphorylated in PHFs. In this study, we report that transient transfection of human GSK3 beta into Chinese hamster ovary cells stably transfected with individual human tau isoforms leads to hyperphosphorylation of tau at all the sites investigated with phosphorylation-dependent anti-tau antibodies. Thus, GSK3 beta is a protein kinase that phosphorylates tau protein in intact cells.
Neurosci Lett 1995 Sep 08
PMID:Glycogen synthase kinase-3 beta phosphorylates tau protein at multiple sites in intact cells. 855 82

Paired helical filaments isolated from the brains of patients with Alzheimer's disease are composed of a major protein component, the microtubule-associated protein termed tau, together with other nonprotein components, including heparan, a glycosaminoglycan, the more extensively sulfated form of which is heparin. As some of these nonprotein components may modulate the assembly of tau into filamentous structures, we have analyzed the ability of the whole tau protein or some of its fragments to self-assemble in the presence of heparin. Different tau fragments, all of them containing some sequences of the tubulin-binding motif, can assemble in vitro into filaments. We have also found formation of polymers with the 18-residue-long peptide corresponding to the third tubulin-binding motif of tau. This suggests that the ability of tau for self-assembly could be localized in a short sequence of amino acids present in the tubulin-binding repeats of the tau molecule.
J Neurochem 1996 Sep
PMID:Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. 875 25

The microtubule-associated protein tau, a major component of paired helical filaments in Alzheimer's disease, had been thought to be a neuron-specific protein. We investigated various rat tissues using both reverse transcriptase-coupled polymerase chain reaction and immunoblotting. tau was found to be widely expressed in many tissues besides the nervous system: at relatively high levels in the heart, skeletal muscle, lung, kidney, and testis and at low levels in the adrenal gland, stomach, and liver. In terms of the tau isoform expression, tissues fall into three classes: those expressing predominantly small tau, those expressing predominantly big tau, and those expressing both at comparable levels. The phosphorylation state of tau varied among the tissues, as shown by differences in the extents of changes in the reactivities with Tau 1 and electrophoretic mobilities after dephosphorylation. It is notable that tau in many nonneural tissues was highly phosphorylated at Ser396 (according to the numbering of the 441-residue human tau isoform). Thus, tau is widely expressed in rat tissues.
J Neurochem 1996 Sep
PMID:Tau is widely expressed in rat tissues. 875 31

Microtubule-associated protein tau is localized to the axon in situ and has been implicated in the development of neuronal polarity. Here we report that tau is extracted differentially in cultured hippocampal neurons yielding an axon-specific localization under conditions that keep the integrity of the plasma membrane. The amount of bound tau increases toward the distal axon and is highest at the transition from the axonal shaft to the growth cone. This distribution is significantly different from the distribution of axonal microtubules that are most concentrated at the proximal axon. Distal binding of tau to one process appears early in development of polarity in culture and correlates with the onset of axon formation (day 2 in culture). Binding to the distal axon requires intact microtubules and microfilaments. Distal tau binding does not stabilize microtubules selectively against drug-induced disassembly, because colchicine-induced microtubule depolymerization is highest distally. We conclude that binding of tau to the distal axon follows a complex mechanism, is an early event in the development of polarity, and reproduces the axon-specific localization of tau in situ.
J Neurosci 1996 Sep 15
PMID:Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. 879 14

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.
J Neurosci 1996 Sep 15
PMID:A spatial gradient of tau protein phosphorylation in nascent axons. 879 28

Alzheimer's disease (AD) is characterized pathologically by two distinguishable deposits in the brain, namely senile plaques and neurofibrillary tangles (NFT). Senile plaques are composed of fragments of the amyloid precursor protein, whereas NFT are composed primarily of paired-helical filaments (PHF). The latter are in turn composed principally of the microtubule-associated protein, tau. Tau in PHF is highly and unusually phosphorylated but the mechanisms leading to this unusual phosphorylation are not known. Using a combination of immunoblotting and kinase assays, we demonstrate that a discreet set of kinases copurify with PHF. One of these kinases was found by immunoblotting to be alpha-calcium-calmodulin-dependent kinase II (alpha-CaM kinase). Immunogold labeling revealed that alpha-CaM kinase was localized to a novel globular membranelike structure found at the ends of PHF. Since previous studies have shown alpha-CaM kinase to be involved in memory, its association with PHF may have important implications in understanding memory loss in AD. We also discuss the possibility that the association of alpha-CaM kinase with PHF may indicate sites where tau protein is converted into PHF.
J Neuropathol Exp Neurol 1996 Sep
PMID:alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer's disease. 880 91

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.
Acta Neuropathol 1996 Sep
PMID:Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. 887 Aug 24

A 53-year-old Japanese woman with a point mutation in mitochondrial DNA (tRNALeu(UUR), nt3243) consistent with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and Alzheimer-type brain pathology is reported. This woman had suffered myopathy and psychosis without any clinical evidence of, stroke-like episodes during the last 10 years of her life, and had died after an accident. At autopsy 30 h post mortem, a part of the brain was snap frozen for biochemical and histochemical studies, and the remaining part was processed for a routine examination and electron microscopy. In the brain there were no ischemic lesions. Instead, primitive/diffuse senile plaques were found throughout the brain, predominantly in the frontal and temporal lobes, while Alzheimer neurofibrillary tangles were found only in the parahippocampal gyrus. These plaques were positive for beta-protein and mostly negative for tau protein, ubiquitin, neurofilaments, alpha-choline acetyltransferase, and acetylcholinesterase. Mutations in codon 331 of the ND2 gene as well as codons 693, 713 and 717 of the beta-amyloid precursor protein gene, known to be responsible for some cases of familial Alzheimer disease, were not found. Furthermore, coincidental Down syndrome was ruled out by chromosome analysis. The results suggest a possible correlation between this mitochondrial DNA abnormality and Alzheimer-type pathology.
Acta Neuropathol 1996 Sep
PMID:Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). 887 Aug 35


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