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)

Neurofibrillary tangles and senile plaques are the characteristic neuropathological lesions of Alzheimer's disease. Neurofibrillary tangles are composed of a microtubule-associated protein, the tau protein. This protein plays a role in the development of neuronal polarity and the stabilisation of microtubules. In Alzheimer's disease, tau proteins are abnormally phosphorylated on several sites. This abnormal phosphorylation might induce the modifications of the microtubule network observed in affected neurones. The main component of the senile plaque is an amyloid deposit made of a polypeptide (beta/A4 amyloid) which derives from a larger precursor. The overexpression of this precursor in experimental models or mutations of its gene leads to the development of neuropathological lesions. The relationships between cytoskeletal abnormalities and beta/A4 amyloid are further discussed.
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PMID:[Cellular lesions in Alzheimer's disease: structural and molecular analysis]. 134 72

The antineoplastic drug estramustine is an adduct of estradiol and nor-nitrogen mustard. It has been shown that this drug interferes with microtubule assembly, an effect mediated by estramustine interaction with microtubule-associated proteins (MAPs). In the present report we demonstrate that estramustine and the phosphorylated derivative of the drug, estramustine-phosphate, inhibit the secretion of interleukin-3 by WEHI-3B cells. These studies also show that the estramustine derivative specifically interacts with a MAPs component found in these cells, which exhibited characteristics ressembling those of tau protein isoforms. Western blots using a unique monoclonal antibody MTB6.22 that recognizes microtubule-binding domains on MAPs, indicated that this WEHI protein factor contained the antigenic determinant that are functionally significant for microtubule assembly. ELISA assays using this antibody, also showed a decrease in the levels of the immunoreactive protein in WEHI cells after treatment with EMP. Interestingly, it has been recently described that the action of estramustine-phosphate is mediated by a direct interaction with MAP-binding sites on the microtubule surface, which are recognized by the site-specific monoclonal antibody. These findings together with immuno-precipitation experiments using anti-interleukin-3 antibodies and the inhibitory effect of the estramustine derivative on WEHI secretion process suggest that this anti-mitotic agent may block IL-3 secretion by a mechanism involving its interaction with a 'tau-like' MAPs component present in these cells.
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PMID:The antineoplastic agent estramustine and the derivative estramustine-phosphate inhibit secretion of interleukin-3 in leukemic cells. Possible roles of MAPs. 148 50

Morphological differentiation of N2A neuroblastoma cells is associated with an altered splicing of the gene of the microtubule-associated protein, tau. Two populations of RNA (coding for tau proteins containing three or four tubulin-binding motifs) are present in a similar proportion in undifferentiated neuroblastoma cells while in differentiated cells the proportion is changed in favour of that population coding for tau protein containing four tubulin-binding motifs. An increase in a high molecular weight tau isoforms correlates with the increase in the RNA population coding for four tubulin-binding motifs. A possible consequence of expressing a higher proportion of the tau protein containing four tubulin-binding motifs could be an increase in microtubule stability of differentiated neuroblastoma cells.
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PMID:Differentiation of neuroblastoma cells correlates with an altered splicing pattern of tau RNA. 154 66

The ways in which the various microtubule-associated proteins (MAPs) contribute to cellular function are unknown beyond the ability of these proteins to modify microtubule dynamics. One member of the MAP family, tau protein, is restricted in its distribution to the axonal compartment of neurons, and has therefore prompted studies that attempt to relate tau function to the generation or maintenance of this structure. Sf9 cells from a moth ovary, when infected with a baculovirus containing a tau cDNA insert, elaborate very long processes. This single gene product expressed in a foreign host cell grossly alters the normal rounded morphology of these cells. The slender, relatively nonbranched appearance of these processes as well as their uniform caliber resembles the light-microscopic appearance of axons observed in several neuronal culture systems. Immunolabeling of the tau-expressing Sf9 cells demonstrated tau reactivity in the induced processes, and EM that microtubule bundles were present in the processes. Microtubule stabilization alone was insufficient to generate processes, since taxol treatment did not alter the overall cell shape, despite the induction of microtubule bundling within the cell body.
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PMID:Overexpression of tau in a nonneuronal cell induces long cellular processes. 167 91

Serum-free aggregating cell cultures of fetal rat telencephalon were examined by biochemical and immunocytochemical methods for their development-dependent expression of several cytoskeletal proteins, including the heavy- and medium-sized neurofilament subunits (H-NF and M-NF, respectively); brain spectrin; synapsin I; beta-tubulin; and the microtubule-associated proteins (MAPs) 1, 2, and 5 and tau protein. It was found that with time in culture the levels of most of these cytoskeletal proteins increased greatly, with the exceptions of the particular beta-tubulin form studied, which remained unchanged, and MAP 5, which greatly decreased. Among the neurofilament proteins, expression of M-NF preceded that of H-NF, with the latter being detectable only after approximately 3 weeks in culture. Furthermore, MAP 2 and tau protein showed a development-dependent change in expression from the juvenile toward the adult form. The comparison of these developmental changes in cytoskeletal protein levels with those observed in rat brain tissue revealed that protein expression in aggregate cultures is nearly identical to that in vivo during maturation of the neuronal cytoskeleton. Aggregate cultures deprived of glial cells, i.e., neuron-enriched cultures prepared by treating early cultures with the antimitotic drug cytosine arabinoside, exhibited pronounced deficits in M-NF, H-NF, MAP 2, MAP 1, synapsin I, and brain spectrin, with increased levels of a 145-kDa brain spectrin breakdown product. These adverse effects of glial cell deprivation could be reversed by the maintenance of neuron-enriched cultures at elevated concentrations of KCl (30 mM). This chronic treatment had to be started at an early developmental stage to be effective, a finding suggesting that sustained depolarization by KCl is able to enhance the developmental expression and maturation of the neuronal cytoskeleton.
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PMID:Development and maintenance of the neuronal cytoskeleton in aggregated cell cultures of fetal rat telencephalon and influence of elevated K+ concentrations. 172 9

Tau, a microtubule-associated protein (MAP) enriched in axons, may have a role in the generation and maintenance of an axonal morphology. Neurons from embryonic day 15 rat cerebellum in culture elaborate two morphologically distinct neurite populations--one with nontapering, elongated axonlike neurites and the other with tapered dendritelike neurites that branch frequently and are selectively stained with antibodies to MAP2. Tau antisense oligonucleotides were utilized in two ways: (1) continuous application of antisense every 24 hr for variable periods of time or (2) application of antisense that was delayed until neurite differentiation was underway. In both cases, 24 hr after the administration of the antisense, tau protein was not detected immunocytochemically. When the antisense was given continuously directly after plating, the neurites persisted as simple minor outgrowths. When antisense was added 72 hr after plating, axonlike neurites were lost, while the remaining neurites continued to grow and increase in complexity. We concluded that the initial establishment of an elongated axonlike neurite is a prerequisite for further neurite maturation; however, once the axon is established, the remaining neurites are able to grow independently and assume a tapered dendritelike appearance.
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PMID:The effect of tau antisense oligonucleotides on neurite formation of cultured cerebellar macroneurons. 190 79

The tau protein is a microtubule-associated protein that is normally located in nerve axons. In Alzheimer disease, it is a constituent of paired helical filaments (PHFs), which are the principal fibrous component of the characteristic neurofibrillary tangles. The tau protein, therefore, is abnormally sequestered in an insoluble form in PHFs in the cell body and dendrites in Alzheimer disease. We have used two monoclonal antibodies (mAbs) to selectively measure the levels of normal, soluble tau protein and of PHF-associated tau protein in the brain. mAb 423 binds to PHFs and recognizes a 12-kDa fragment of tau protein released by formic acid treatment of PHFs, but it does not recognize normal tau protein. In contrast, mAb 7.51 recognizes normal tau protein as well as the PHF core-derived tau fragment, but its epitope is concealed in the PHF-bound form. The differential binding properties for these two mAbs have enabled us in this study to quantify insoluble PHF-associated tau protein in the somatodendritic compartment as well as normal soluble tau protein in its predominantly axonal location. Our findings demonstrate that a distinct immunochemical presentation of tau protein recognized by mAb 423, a PHF-specific marker, can be used to quantify neurofibrillary pathology in Alzheimer disease independently of the presence of normal tau proteins.
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PMID:Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease. 190 17

Synthetic peptides have been used to define the consensus amino acid sequence for substrate recognition by the meiosis-activated myelin basic protein (MBP) kinase (p44mpk), which was purified from maturing sea star oocytes. This protein kinase shares many properties with the mitogen-activated microtubule-associated protein-2 kinase (p42mapk) in vertebrates. Recently, Thr-97 in the tryptic fragment KNIVTPRTPPPSQGK of bovine MBP was identified as the major site of phosphorylation by p44mpk (Sanghera, J. S., Aebersold, R., Morrison, H. D., Bures, E. J., and Pelech, S. L. (1990) FEBS Lett. 273, 223-226). Synthetic peptides modeled after this sequence revealed that the presence of a proline residue C-terminal (+1 position) to the phosphorylatable threonine (or serine) residue was critical for recognition by p44mpk. Although not essential, a proline residue located at the -2 position enhanced the Vmax of peptide phosphorylation. Basic, acidic, and non-polar residues were equally tolerated at the -1 position. The presence of an amino acid residue at position -3 also increased peptide phosphorylation. Thus, the optimum consensus sequence for phosphorylation by p44mpk was defined as Pro-X-(Ser/Thr)-Pro, where X is a variable amino acid residue, but ideally not a Pro. Peptides that included this sequence were phosphorylated by p44mpk with Vmax values approaching 1 mumol.min-1.mg-1 and with apparent Km values of approximately 1 mM). Pseudosubstrate peptides in which the phosphorylatable residue was replaced by valine or alanine were weak inhibitors of p44mpk (apparent Ki values of approximately 3 mM). Over 40 distinct protein kinases contain Pro-X-(Ser/Thr)-Pro sequences including the human receptors for insulin and epidermal growth factor, and kinases encoded by the human proto-oncogenes abl, neu, and raf-1, and Schizosaccharomyces pombe cell cycle control genes ran-1 and wee-1. Multiple putative sites were also identified in rat microtubule-associated protein-2, human retinoblastoma protein, human tau protein, and Drosophila myb protein and RNA polymerase II.
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PMID:Definition of a consensus sequence for peptide substrate recognition by p44mpk, the meiosis-activated myelin basic protein kinase. 190 71

Many of the human neurodegenerative conditions involve a reorganization of the neuronal cytoskeleton. The way in which the cytoskeleton is reorganized may provide a clue to the nature of the insult causing the neurodegeneration. The most common of these conditions is Alzheimer's disease, in which microtubules are lost from neurites that fill up with filamentous structures. One component of the filamentous structures is the microtubule-associated protein (MAP), tau. The tau protein is the product of a single gene expressed predominantly in neurons. The tau gene undergoes complex alternative splicing that is regulated both by development, and by the particular neuronal cell population in which it is expressed. Tau protein can be further modified, following its translation by phosphorylation at several sites. Much of the recent interest in the transition of tau to an abnormal state within a tangle-bearing neuron has focused on phosphorylation. A group of proteins that migrate slightly more slowly than tau, designated PHF-tau, are found in regions of the Alzheimer brain rich in dystrophic neurites, are hyperphosphorylated, fail to bind to microtubules, have distinct solubility properties, and can be derived from fractions of paired helical filaments (PHF).
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PMID:Tau protein and neurodegeneration. 213 93

Paired helical filaments (PHF) are unusual neuronal fibers which accumulate progressively in the brain in Alzheimer's disease (AD). The insolubility of PHF in various kinds of solvents enabled us to obtain highly purified PHF, but prevented the application of conventional analytical methods to identify their components. Here we report that antibodies against purified PHF recognize tau protein, a brain-specific microtubule-associated protein, suggesting that a portion of PHF is tau protein.
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PMID:One of the antigenic determinants of paired helical filaments is related to tau protein. 242 12


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