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)

Oligodendrocytes in culture are characterized by large membranous sheets containing an elaborate network of microtubules. Microtubule-associated proteins (MAPs) participate in microtubule stability and the regulation of the cellular architecture. We have investigated the expression of two major groups of MAPs, MAP2 and tau, in cultured rat brain oligodendrocytes. Alternatively spliced isoforms of mRNAs encoding MAP2 and tau were assessed by means of reverse transcription and polymerase chain reaction using a newly designed set of MAP2- and tau-specific primers. The data were compared with data obtained with cultures of rat brain astrocytes and rat cerebral neurons, and adult rat brain. The results show that oligodendrocytes, similarly to neurons, express mainly MAP2c transcripts containing three microtubule-binding repeats. They also contain small amounts of MAP2b mRNA. Six low molecular weight tau isoforms, namely tau 1-6, have been described in the brain (Goedert et al. 1991). The major isoform of tau mRNA in oligodendrocytes was found to be tau 1, which represents a marker typical for immature neurons. Tau 2 and tau 4 isoforms were also detected, albeit at a very low level. Immunoblot analysis of oligodendroglia cell extracts confirmed the presence of tau protein. It migrates as a single polypeptide with an apparent molecular weight of approximately 55 kDa. In addition, oligodendrocytes express MAP2c protein, which migrates as a close double band with an apparent molecular weight around 70 kDa. Indirect immunofluorescence staining indicated that tau and MAP2 immunoreactivity was expressed in oligodendrocytes of immature and mature morphologies in the cell somata and cellular processes. Tau was particularly found in the end of the cellular extensions, and both proteins exhibited a distribution similar to myelin basic protein. Thus, oligodendroglia, like neuronal cells, contain microtubule-associated proteins, mainly MAP2c and the tau 1 isoform, although at a much lower level. The presence of these MAPs in myelin-forming cells further points to the functional significance of the cytoskeleton during oligodendrocyte differentiation, process outgrowth, and myelin formation.
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PMID:Expression of microtubule-associated proteins MAP2 and tau in cultured rat brain oligodendrocytes. 908 59

Quantitative blot immunolabeling techniques were used to compare the effect of cold water stress (CWS) on the phosphorylation of brain tau protein in two strains of C57BL/6J mice: ob/ob and ob/+. CWS induced immediate, significant (4-6 fold) and continuous accumulation of Alzheimer's like forms of tau phosphorylated at Ser 202. The effect was considerably (150-200%) higher in ob/ob mice compared to ob/+ mice. By contrast, the unphosphorylated tau immunoreactivity decreased after the CWS, whereas no changes were detected in the abundance of several other antigens. The level of anti Erk 1 + 2 immunoreactivity corresponding to 36-37 kDa polypeptide was 2-3 fold higher in ob/ob than in ob/+ mice. No strain differences were detected in the abundance of several other protein kinases. Obtained results support the hypothesis that Erk 1 or 2 like protein kinase may be involved in the restructuring of neuronal cytoskeleton in response to environmental stress.
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PMID:Stress-induced tau phosphorylation in mouse strains with different brain Erk 1 + 2 immunoreactivity. 982 Nov 59

The diagnosis of Alzheimer's disease (AD), the most common form of dementia in the general population, usually relies upon the presence of typical clinical features and structural changes on brain magnetic resonance imaging. Over the last decade, a number of biological abnormalities have been reported in the cerebrospinal fluid (CSF) of AD patients, in particular altered levels of the tau protein and the 1-42 fragment of the amyloid precursor protein. These, however, have not yet proved sensitive and specific enough to be included in the diagnostic criteria for AD, leaving plenty of room for the search of novel biomarkers. The present study describes the analysis of CSF polypeptides by a protein-chip array technology called surface enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS). Using this approach, we detected statistically significant quantitative differences (p < 0.05) regarding four overexpressed and one underexpressed polypeptides in the CSF of AD patients as compared to healthy controls. Four of them were further purified by strong anionic exchange chromatography (SAX) and identified by MS analysis as cystatin C, two beta-2-microglobulin isoforms, an unknown 7.7 kDa polypeptide, and a 4.8 kDa VGF polypeptide. The combination of the five polypeptides for the diagnosis of AD allowed to classified six AD patients out of the nine included in this study and all the ten controls, which means in this small cohort that the specificity and sensitivity are 100% and 66%, respectively. This study, based on the protein-chip array technology, demonstrates the presence in the CSF of novel potential biomarkers for AD, which may be used for the diagnosis and perhaps the assessment of the severity and progression of the disease.
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PMID:A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. 1292 74

ncd is a minus-end directed, kinesin-like motor, which binds to microtubules with its motor domain and its cargo domain as well. Typical of retrograde motors, the motor domain of ncd locates to the C-terminal end of the polypeptide chain, and hence, the cargo domain constitutes the N-terminal region. To date, several studies have investigated the interaction properties of the motor domain with microtubules, but very few structural data are available about the tail itself or its interaction with microtubules as cargo. Here, we applied cryo-electron microscopy and helical 3D image reconstruction to 15 protofilament microtubules decorated with an ncd tail fragment (N-terminal residues 83-187, named NT6). In our study, the ncd tail shows a behaviour resembling filamentous MAPs such as tau protein, exhibiting a highly flexible structure with no large globular domains. NT6 binds to four different sites on the outer side of microtubules within the proximity of the kinesin motor-binding site. Two of these sites locate within the groove between two neighbouring protofilaments, and appear as strong binding sites, while the other two sites, located at the outer rim, appear to play a secondary role. In addition, the ncd tail fragment induces the formation of large protofilament sheets, suggesting a tail-induced modification of lateral protofilament contacts.
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PMID:A structural analysis of the interaction between ncd tail and tubulin protofilaments. 1455 43

The microtubule-associated protein tau is found aggregated into paired helical filaments in the intraneuronal neurofibrillary tangle deposits of victims of Alzheimer's disease (AD) and other related dementias. Tau contains a repeat domain consisting of three or four 31-32-residue imperfect repeats that forms the core of tau filaments and is capable of self-assembling into filaments in vitro. We have used high-resolution NMR spectroscopy to characterize the structural properties of the three-repeat domain of tau at the level of individual residues. We find that three distinct regions of the polypeptide corresponding to previously mapped microtubule interaction sites exhibit a preference for helical conformations, suggesting that these sites adopt a helical structure when bound to microtubules. In addition, we directly observe a marked preference for extended or beta-strand-like conformations in a stretch of residues between two of the helical regions, which corresponds closely to a region previously implicated as an early site of beta-strand structure formation and intermolecular interactions leading to paired helical filament (PHF) formation. This observation supports the idea that this region of the protein plays a crucial role in the formation of tau aggregates. We further show that disulfide-bond-mediated dimer formation does not affect and is not responsible for the observed structural preferences of the protein. Our results provide the first high-resolution view of the structural properties of the protein tau, are consistent with an important role for beta structure in PHF formation, and may also help explain recent reports that tau filaments contain helical structure.
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PMID:Residual structure in the repeat domain of tau: echoes of microtubule binding and paired helical filament formation. 1565 59

1. Several intrinsically disordered proteins (IDPs) play principal role in the neurodegenerative processes of various types. Among them, alpha-synuclein is involved in Parkinson's disease, prion protein in transmissible spongiform encephalopathies, and tau protein in Alzheimer's disease (AD) and related tauopathies. Neuronal damage in AD is accompanied by the presence of tau protein fibrils composed of paired helical filaments (PHF). 2. Tau protein represents a typical IDP. IDPs do not exhibit any stable secondary structure in the free form, but they are able to fold after binding to targets and contain regions with large propensity to adopt a defined type of secondary structure. Binding-folding event at tau protein leading to PHF generation is believed to happen in the course of tauopathies. 3. Detailed molecular topology of PHF formation is unknown. There are evidences about the cross-beta structure in PHF core; however the precise arrangement of the tau polypeptide chain is unclear. In this review we summarize current attempts at in vitro PHF reconstruction and the development of methods for PHF structure determination. The emphasis is put on the monoclonal antibodies used as structural molecular probes for research on the role of IDPs in pathogenesis of neurodegenerative diseases.
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PMID:Intrinsically disordered proteins in the neurodegenerative processes: formation of tau protein paired helical filaments and their analysis. 1677 70

Alzheimer's disease (AD) is a common neurodegenerative disorder that presents clinically as inexorable cognitive impairment and decline in performance of activities of daily living. AD is characterized pathologically by neuronal depopulation, extracellular amyloid plaques, and intraneuronal accumulation of neurofibrillary tangles (NFTs). Accumulation of these polypeptide aggregates is generally believed to be integral to the pathogenesis of AD. Recent evidence implicates the protein kinase glycogen synthase kinase 3 (GSK-3) in the regulation of both of these processes. GSK-3 has long been studied as one of several tau protein kinases, and has more recently been shown to be involved in the generation of Abeta peptides. GSK-3 activity may also promote cell death and conversely, inhibition of GSK-3 has been associated with increased cell survival under a variety of cytotoxic conditions. Thus drugs that target GSK-3 could attack AD pathogenesis on multiple fronts simultaneously. Here we will briefly review the molecular understanding of AD pathogenesis as it stands at this point, and then discuss the emerging role of GSK-3 in regulating these processes.
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PMID:Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease. 1710 May 79

Cortical neurons are vulnerable to ischemic insult, which may cause cytoskeletal changes and neurodegeneration. Tau is a microtubule-associated protein expressed in neuronal and glial cells. We examined the phosphorylation status of tau protein in the gerbil brain cortex during 5 min ischemia induced by bilateral common carotid artery occlusion followed by reperfusion for 20 min to 7 days. Control brain homogenates contained 63, 65 and 68 kD polypeptides of tau immunoreactive with Alz 50, Tau 14 and Tau 46 antibodies raised against non-phosphorylated tau epitopes. Gerbil tau was also immunoreactive with some (PHF-1 and 12E8) but not all (AT8, AT100, AT180 and AT270) antibodies raised against phosphorylated tau epitopes. PHF-1 recognized a single 68 kD polypeptide and 12E8 bound the 63 kD polypeptide. During 5 min ischemia, PHF-1 immunoreactivity declined to 6%, then recovered to control levels after 20 min of blood recirculation and subsequently increased above control values 3 and 7 days later. In contrast, 12E8 immunoreactivity remained stable during ischemia and reperfusion. Our results suggest that the two phosphorylated epitopes of tau are regulated by different mechanisms and may play different roles in microtubule dynamics. They may also define various pools of neuronal/glial cells vulnerable to ischemia.
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PMID:Differential changes in phosphorylation of tau at PHF-1 and 12E8 epitopes during brain ischemia and reperfusion in gerbils. 1719 Nov 39

Mutations in the MAPT gene encoding tau protein lead to neurofibrillary lesion formation, neurodegeneration, and cognitive decline associated with frontotemporal lobar degeneration. While some pathogenic mutations affect MAPT introns, resulting in abnormal splicing patterns, the majority occur in the tau coding sequence leading to single amino acid changes in tau primary structure. Depending on their location within the polypeptide chain, tau missense mutations have been reported to augment aggregation propensity. To determine the mechanisms underlying mutation-associated changes in aggregation behavior, the fibrillization of recombinant pathogenic mutants R5L, G272V, P301L, V337M, and R406W prepared in a full-length four-repeat human tau background was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods. Kinetic constants for nucleation and extension phases of aggregation were then estimated by direct measurement and mathematical simulation. Results indicated that the mutants differ from each other and from wild-type tau in their aggregation propensity. G272V and P301L mutations increased the rates of both filament nucleation and extension reactions, whereas R5L and V337M increased only the nucleation phase. R406W did not differ from wild-type in any kinetic parameter. The results show that missense mutations can directly promote tau filament formation at different stages of the aggregation pathway.
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PMID:Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. 1880 94

A simple method for differentiating human-derived SH-SY5Y neuroblastoma cells to provide a stable, mature, neuronal morphology is described. SH-SY5Y cells can be induced to differentiate terminally with retinoic acid in medium with low levels of serum. The morphological differentiation of the parental cell line SK-N-SH was compared with that seen in the SH-SY5Y cells. Changes in the cytoskeleton of SH-SY5Y cells indicated that differentiation proceeds continuously over the 1-month period studied after initiating differentiation. Immunoblot analysis demonstrated increased expression of the high molecular weight neurofilament polypeptide NF-H, the microtubule-associated protein tau, and the synaptic vesicle-associated protein synapsin I, indicating that an increasingly mature, neuronal phenotype was being expressed. The cultures were not dependent on retinoic acid for continued survival. SH-SY5Y cultures differentiated over extended periods should provide a good in vitro model for studying the neurotoxic potential of compounds and mechanisms of toxicity, particularly in longer-term or multiple exposure studies, for example on cytoskeletal function, where acute toxicity is not the aspect of interest.
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PMID:Phenotypic morphology and the expression of cytoskeletal markers during long-term differentiation of human SH-SY5Y neuroblastoma cells. 2065 Feb 35


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