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)

Tauopathies, including Alzheimer's disease, are neurodegenerative disorders in which tau protein accumulates as a consequence of alterations in its metabolism. At least three different types of alterations have been described; in some cases, an aberrant mRNA splicing of tau exon 10 occurs; in other cases, the disorder is a consequence of missense mutations and, in most cases, aberrant tau hyperphosphorylation takes place. Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the etiology of Alzheimer's disease and other tauopathies. Here, we have evaluated whether GSK-3 is also able to modulate tau-mRNA splicing. Our data demonstrate that GSK-3 inhibition in cultured neurons affects tau splicing resulting in an increase in tau mRNA containing exon 10. Pre-mRNA splicing is catalyzed by a multimolecular complex including members of the serine/arginine-rich (SR) family of splicing factors. Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase. Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3beta. Phosphorylation of a peptide from the SR domain by GSK-3 revealed that the peptide needs to be prephosphorylated, suggesting the involvement of a priming kinase. Our results demonstrate that GSK-3 plays a crucial role in tau exon 10 splicing, raising the possibility that GSK3 could contribute to tauopathies via aberrant tau splicing.
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PMID:Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease. 1460 10

The serine/threonine phosphatase 2A (PP2A) has been implicated in the pathogenesis of Alzheimer's disease (AD) due to its important role in regulating dephosphorylation of the microtubule-associated protein tau and mitogen-activated protein (MAP) kinase. In the present study, we show that PP2A was responsible for dephosphorylation of the extracellular signal-regulated kinase 1/2 (Erk1/2) following its activation by BK stimulation. Abnormal gene and protein expressions of PP2A, as well as its activity, were found to contribute to the abnormally prolonged Erk1/2 phosphorylation in the AD fibroblasts. Inhibition of PP2A with okadiac acid produced enhanced and more lasting Erk1/2 phosphorylation after BK stimulation, whereas FK506, an inhibitor of PP2B and FK-binding protein, inhibited the BK-stimulated Erk1/2 phosphorylation. Furthermore, while the phosphorylated Erk1/2 was concentrated in the nucleus of AC cells, it was mainly distributed in the extranuclear compartments of AD cells. These results suggest that the delayed dephosphorylation of Erk1/2 in AD cells following its BK-stimulated activation may be due to deficits of PP2A activity and impaired nuclear translocation of phosphorylated Erk1/2.
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PMID:Impairment of phosphatase 2A contributes to the prolonged MAP kinase phosphorylation in Alzheimer's disease fibroblasts. 1467 62

Filamentous tau protein deposits are a pathological hallmark of a group of neurodegenerative disorders (tauopathies). Tau protein in these aggregates is highly phosphorylated at different phosphorylation sites. Although tau filaments can be formed by heparin-induced aggregation of unphosphorylated recombinant tau, it is not known how tau phosphorylation modulates aggregation behaviour. Analysis of the effect of tau phosphorylation at defined single or multiple sites is hampered by the low specificity of protein kinases and the highly dynamic turnover of phosphorylation in vivo. To overcome this problem we employed site-directed mutagenesis to convert serine and threonine to aspartic acid or glutamic acid, which introduce a negative charge and conformational change that mimic phosphorylation. We tested 14 different mutated tau proteins for their propensity for self-aggregation and formation of tau filaments. Tau aggregation was monitored with thioflavin S fluorescence in the presence of different inducers such as heparin, Al3+, Fe2+ and Fe3+. We found that mutations in the N-terminal portion up to amino acid 208 mainly suppress tau aggregation, whereas mutations in the C-terminal region mainly lead to an enhanced aggregation. Mutations in the middle portion of tau showed a mixed picture of suppression and enhancement of aggregation. A single amino acid change Ser422Glu has aggregation-favouring properties with all four inducers.
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PMID:Pseudophosphorylation of tau protein alters its ability for self-aggregation. 1500 52

Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.
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PMID:Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease. 1501 15

An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer's disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231)) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau(181)) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau(231) levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks.
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PMID:Total and phosphorylated tau proteins: evaluation as core biomarker candidates in frontotemporal dementia. 1517 52

Mutations that stimulate exon 10 inclusion into the human tau mRNA cause frontotemporal dementia with parkinsonism, associated with chromosome 17 (FTDP-17), and other tauopathies. This suggests that the ratio of exon 10 inclusion to exclusion in adult brain is one of the factors to determine biological functions of the tau protein. To investigate the underlying splicing mechanism and identify potential therapeutic targets for tauopathies, we generated a series of mini-gene constructs with intron deletions from the full length of tau exons 9-11 mini-gene construct. RT-PCR results demonstrate that there is a minimum distance requirement between exon 10 and 11 for correct splicing of the exon 10. In addition, SRp20, a member of serine-arginine (SR) protein family of splicing factors was found to facilitate exclusion of exon 10 in a dosage-dependent manner. Significantly, SRp20 also induced exon 10 skipping from pre-mRNAs containing mutations identified in FTDP-17 patients. Based on those results, we generated a cell-based system to measure inclusion to exclusion of exon 10 in the tau mRNA using the luciferase reporter. The firefly luciferase was fused into exon 11 in frame, and a stop code was also created in exon 10. Inclusion of exon 10 prevents luciferase expression, whereas exclusion of exon 10 generates luciferase activity. To minimize baseline luciferase expression, our reporter construct also contains a FTDP-17 mutation that increases exon 10 inclusion. We demonstrate that the splicing pattern of our reporter construct mimics that of endogenous tau gene. Co-transfection of SRp20 and SRp55, two SR proteins that promote exon 10 exclusion, increases production of luciferase. We conclude that this cell-based system can be used to identify biological substances that modulate exon 10 splicing.
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PMID:A minimal length between tau exon 10 and 11 is required for correct splicing of exon 10. 1519 76

Microtubule-associated protein tau in a hyperphosphorylated state is the major component of the filamentous lesions that define a number of neurodegenerative diseases commonly referred to as tauopathies. Hyperphosphorylation of tau at most sites appears to precede filament assembly. Many of the hyperphosphorylated sites are serine/threonine-proline sequences. Here we show that c-Jun N-terminal kinases JNK1, JNK2 and JNK3 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Of the three protein kinases, JNK2 phosphorylated the most sites in tau, followed by JNK3 and JNK1. Phosphorylation by JNK isoforms resulted in a greatly reduced ability of tau to promote microtubule assembly. These findings extend 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 isoforms of c-Jun N-terminal kinase (JNK). 1522 92

Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains of individuals with Alzheimer's disease (AD) and other tauopathies. Tau pathology is critical to pathogenesis and correlates to the severity of dementia. However, the mechanisms leading to abnormal hyperphosphorylation are unknown. Here, we demonstrate that human brain tau was modified by O-GlcNAcylation, a type of protein O-glycosylation by which the monosaccharide beta-N-acetylglucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond. O-GlcNAcylation regulated phosphorylation of tau in a site-specific manner both in vitro and in vivo. At most of the phosphorylation sites, O-GlcNAcylation negatively regulated tau phosphorylation. In an animal model of starved mice, low glucose uptake/metabolism that mimicked those observed in AD brain produced a decrease in O-GlcNAcylation and consequent hyperphosphorylation of tau at the majority of the phosphorylation sites. The O-GlcNAcylation level in AD brain extracts was decreased as compared to that in controls. These results reveal a mechanism of regulation of tau phosphorylation and suggest that abnormal hyperphosphorylation of tau could result from decreased tau O-GlcNAcylation, which probably is induced by deficient brain glucose uptake/metabolism in AD and other tauopathies.
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PMID:O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. 1524 77

Alzheimer's disease (AD) is characterized histopathologically by beta-amyloid-containing plaques, neurofibrillary tangles (NFT), reduced synaptic density, and neuronal loss in selected brain areas. Plaques consist of aggregates of a small peptide termed Abeta which is derived by proteolysis of the larger amyloid precursor protein APP, whereas NFT are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Tau pathology in the presence of scant or no beta-amyloid plaques characterizes additional neurodegenerative disorders collectively called tauopathies. In the course of plaque and NFT formation, the major proteinaceous components of these lesions undergo post-translational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). This review aims to provide insight into the complexity of tau modifications in human tauopathies such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Selected aspects of the post-translational modification of tau have been reproduced in transgenic animal models. Most of this work has been done in mice, but insight has also been gained from studies in the sea lamprey, the nematode C. elegans and Drosophila. Attempts have been made to link specific post-translational modifications with tau aggregation and nerve cell dysfunction.
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PMID:Posttranslational modifications of tau--role in human tauopathies and modeling in transgenic animals. 1527 Jan 97

The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.
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PMID:Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. 1547 61


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