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)

Pick bodies and ballooned cells of Pick's disease and the neurofibrillary lesions of Alzheimer's disease are characterized by the presence of hyperphosphorylated microtubule-associated protein tau. Little is known about the mechanisms underlying tau hyperphosphorylation in Pick's disease and the distribution of abnormal tau in affected neurons. We have used a panel of phosphorylation-dependent (AT270, AT8, AT180, 12E8, PHF-1, AT10 and Tau-1) and phosphorylation-independent anti-tau antibodies (N-tau 5 and 134) to stain brain tissue sections from subjects with Pick's disease and Alzheimer's disease. These antibodies labeled Pick bodies and neurofibrillary lesions in a similar way, with the exception of antibody 12E8, which stained a subset of neurofibrillary tangles, but no Pick bodies. Moreover, abundant AT8- and PHF-1-positive neuritic profiles were observed in cortical areas rich in Pick bodies, even in the complete absence of neurofibrillary lesions. Unlike the Gallyas-positive neuropil threads of Alzheimer's disease, which were of variable diameter and covered by spiny appendages, neuritic profiles of Pick's disease showed a regular diameter, appeared smooth and were Gallyas-negative. In contrast to Alzheimer's disease, dendritic branches of neurons containing Pick bodies were not labeled by anti-tau antibodies. In the hippocampus, numerous tau-positive axon terminals were found along dendrites of the polymorphic layer of the dentate gyrus. Our results indicate that tau proteins in Pick's disease and Alzheimer's disease share similar phosphorylated residues, with the exception of serine 262, which is phosphorylated in Alzheimer tangles but not in Pick bodies or neuritic profiles. Furthermore, we show that hyperphosphorylated tau segregates to different neuronal compartments in the two diseases, with a somatoaxonal distribution in Pick's disease and a somatodendritic distribution in Alzheimer's disease.
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PMID:Pick's disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. 896 Mar 16

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.
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PMID:Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein. 897 80

A block method for the solid phase synthesis (SPPS) of serine phosphopeptides has been developed using a combination of Fmoc and Alloc strategies. Alloc-Ser[PO(OCH2CH CH2)2] OH2, prepared in a one pot procedure from Alloc-Ser-OH, was introduced at the N-terminus of a sequence prepared by standard Fmoc-SPPS. Global cleavage of the allyl ester based protecting groups, followed by coupling of a tripeptide fragment, led to the tau phosphopeptide, 1. Using tau phosphopeptides a series of phosphorylation state-dependent antisera to human tau protein have been raised. These antisera are valuable tools for studying the tau protein which is found in an abnormal, hyperphosphorylated form in Alzheimer's disease brain.
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PMID:Combined Fmoc-Alloc strategy for a general SPPS of phosphoserine peptides; preparation of phosphorylation-dependent tau antisera. 904 66

Microtubule-associated protein tau is a neuronal phosphoprotein that promotes microtubule assembly in vitro and has been shown to play a role in the development of axonal morphology. Tau can be phosphorylated in vitro by several kinases, some of which cause a change in the conformation and activities of tau. Here we report the consequences of converting two of the protein kinase A phosphorylation sites (positions 156 and 327), first to alanine to eliminate phosphorylation, and second to aspartate, to mimic phosphorylation. We show that a serine to aspartate mutation at position 327 results in a conformational change similar to that caused by phosphorylation of this residue. This mutation does not affect the activities of tau in microtubule assembly as compared with wild-type tau. However, an additional mutation at position 156 to aspartate drastically decreases the microtubule nucleation activity of tau but does not affect the activity of tau to promote microtubule growth. All constructs are similarly bound to microtubules and promote process formation when expressed in cytochalasin-treated PC12 cells. We conclude that serine to aspartate mutations provide a useful system for analyzing the effect of individual phosphorylation sites on the conformation and function of tau in vitro and in cells. The results provide evidence that microtubule growth and nucleation can be differentially affected by phosphorylation of individual residues in a region amino-terminally flanking the microtubule binding domain of tau.
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PMID:Conversion of serine to aspartate imitates phosphorylation-induced changes in the structure and function of microtubule-associated protein tau. 907 70

A proportion of the neuronal microtubule-associated protein (MAP) tau is highly phosphorylated in foetal and adult brain, whereas the majority of tau in the neurofibrillary tangles of Alzheimer's patients is hyperphosphorylated; many of the phosphorylation sites are serines or threonines followed by prolines. Several kinases phosphorylate tau at such sites in vitro. We have now shown that purified recombinant stress-activated protein kinase/c-Jun N-terminal kinase, a proline-directed kinase of the MAP kinase extended family, phosphorylates recombinant tau in vitro on threonine and serine residues. Western blots using antibodies to phosphorylation-dependent tau epitopes demonstrated that phosphorylation occurs in both of the main phosphorylated regions of tau protein. Unlike glycogen synthase kinase-3, the c-Jun N-terminal kinase readily phosphorylates Thr205 and Ser422, which are more highly phosphorylated in Alzheimer tau than in foetal or adult tau. Glycogen synthase kinase-3 may preferentially phosphorylate the sites found physiologically, in foetal and to a smaller extent in adult tau, whereas stress-activated/c-Jun N-terminal kinase and/or other members of the extended MAP kinase family may be responsible for pathological proline-directed phosphorylations. Inflammatory processes in Alzheimer brain might therefore contribute directly to the pathological formation of the hyperphosphorylated tau found in neurofibrillary tangles.
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PMID:Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. 908 48

Glutamate toxicity has been involved in the pathophysiology of a large variety of neurodegenerative disorders. Tau Protein is a micro-tubule-associated protein that promotes microtubule polymerization and stabilization. Phosphorylated tau protein accumulates in paired helical neurofilaments, the major constituent of neurofibrillary tangles observed in the brain of patients suffering from Alzheimer disease (AD). In this study, using confocal laser microscopy and immunoblot analysis, we report that acute (500 mu M for 15 min) or chronic (20 mu M for 16 h) N-methyl-D-aspartate (NMDA) neuronal toxicities modify the immunoreactivity of phosphorylated tau. Neuronal degeneration produced by N-methyl-D-aspartate is associated with an augmented immunolabeling of phosphorylated tau proteins at serine 202 (AT8 antibody) as observed in paired helical neurofilaments. This finding could help to determine the cellular mechanisms at the origin of neuronal degeneration associated with modifications of phosphorylated tau immunoreactivity produced by receptor-mediated extracellular signals.
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PMID:Modifications of neuronal phosphorylated tau immunoreactivity induced by NMDA toxicity. 914 12

To study the effects of phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) on the ability of the microtubule-associated protein tau to promote microtubule self-assembly, tau isoform 1 (foetal tau) and three mutant forms of this tau isoform were investigated. The three mutant forms of tau had the following serine residues, known to be phosphorylated by GSK-3, replaced with alanine residues so as to preclude their phosphorylation: (1) Ser-199 and Ser-202 (Ser-199/202-->Ala), (2) Ser-235 (Ser-235-->Ala) and (3) Ser-396 and Ser-404 (Ser-396/404-->Ala). Wild-type tau and the mutant forms of tau were phosphorylated with GSK-3beta, and their ability to promote microtubule self-assembly was compared with the corresponding non-phosphorylated tau species. In the non-phosphorylated form, wild-type tau and all of the mutants affected the mean microtubule length and number concentrations of assembled microtubules in a manner consistant with enhanced microtubule nucleation. Phosphorylation of these tau species with GSK-3beta consistently reduced the ability of a given tau species to promote microtubule self-assembly, although the affinity of the tau for the microtubules was not greatly affected by phosphorylation since the tau species remained largely associated with the microtubules. This suggests that the regulation of microtubule assembly can be controlled by phosphorylation of tau at sites accessible to GSK-3beta by a mechanism that does not necessarily involve the dissociation of tau from the microtubules.
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PMID:Phosphorylation of tau by glycogen synthase kinase 3beta affects the ability of tau to promote microtubule self-assembly. 916 8

The paired helical filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the hyperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1gamma (also called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SAPK2b (also called p38beta), SAPK3 (also called ERK6 and p38gamma) and SAPK4 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Based on initial rates of phosphorylation, tau was found to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1gamma. Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly. These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
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PMID:Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. 919 4

Granulovacuolar degeneration (GVD) and neurofibrillary tangles (NFT) are neuropathological features in Alzheimer's disease (AD). The molecular mechanism of GVD formation remains unknown. Recent immunohistochemical investigations suggested a potential link of NFT to GVD formation. Enzyme histochemical studies and electronmicroscopic findings suggested that GVD is formed through lysosomal autophagy of intraneuronal substances. We recently demonstrated that in non-demented cases NFT was phosphorylated at serines 199, 202 and 422 in paired helical filament (PHF)-tau more than in serine 396, while NFT in AD cases was similarly phosphorylated at these four sites in tau. In this study, we demonstrated immunohistochemically a similar phosphorylation state of tau in GVD granules to that in NFT in both non-demented cases and AD patients by using a mouse monoclonal anti-tau antibody and three phosphorylation site-specific antibodies for PHF-tau, indicating that GVD granules and NFT are composed of similar phosphorylated-tau. However, we could not detect PHF structures within any GVD using electronmicroscopy, indicating that PHF itself is not phagocytized by lysosomes during GVD formation. Therefore, the source of GVD granules might be phosphorylated pre-PHF-tau.
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PMID:Immunohistochemical examination of phosphorylated tau in granulovacuolar degeneration granules. 920 60

The microtubule-associated protein tau of normal brains is attached to tubulin through its 18-amino-acid repeat units. In the paired helical filaments (PHF) of Alzheimer's disease, however, tau is oligomerized in an abnormally hyperphosphorylated from (PHF-tau). tau contains two cysteine residues in repeat units 2 and 3, but only the R3-R3 homodimer is present in PHF-tau. A serine residue two amino acids downstream of the R3 cysteine is a major phosphate acceptor site for protein kinase C. In the work repeated here, we used synthetic peptides corresponding to R2, R3 and phosphorylated R3 to determine the binding of the tau repeat peptides to a peptide fragment corresponding to the C-terminal domain of beta-tubulin and to study the kinetics of homo- and heterodimer formation. Additionally, we studied two major biochemical properties of the peptides that distinguish between normal tau and PHF-tau: conformation and metabolic stability. All R2 and R3 peptides bound specifically to the tubulin peptide regardless of the state of phosphorylation or dimerization. The reverse-turn conformation of the tau repeat peptides in the presence of the tubulin peptide remained unaffected. Phosphorylation slightly loosened the turn structure of the monomeric and dimeric peptides, and did not univocally affect the serum stability of the peptides or the ability of the peptides to form dimers. The isolated R2 and R3 units formed homodimers approximately in the same rate. When the two peptides were mixed, however, the R2-R3 heterodimer was formed preferentially over the homodimers. The dimers were generally more stable in human serum than the monomers. Our results with the synthetic peptide fragments of tau indicate that neither oxidation nor phosphorylation of the repeat units is able to generate extended structure such as that found in PHF-tau. Additionally, phosphorylation of Ser324 does not appear to modulate the kinetics of oligomerization of tau, and in general biochemistry terms, does not affect disulfide bridge formation nearby. In agreement with studies at the full-protein level, the formation of homodimers of the peptides, a model of the self-association of tau, is not preferred. If the dimers are formed, however, their clearance is considerably slower than that of the monomers, explaining the remarkable protease resistance of PHF-tau in the affected brains.
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PMID:Oxidized and phosphorylated synthetic peptides corresponding to the second and third tubulin-binding repeats of the tau protein reveal structural features of paired helical filament assembly. 927 97


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