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)

How tau mutations lead to neurodegeneration is unknown but may be related to altered microtubule binding properties of mutant tau protein. The tendency for the mutations to cluster around the microtubule-binding domain of tau or to alter the ratios of those splice isoforms that affect binding supports the view that the tau/microtubule interaction is critical and finely regulated. In cells transfected with both mutant and wild-type tau isoforms fused to either yellow fluorescent protein or cyan fluorescent protein we can observe tau fusion proteins that differ by a single amino acid or by the inclusion or exclusion of exon 10. With coexpression of mutant and wild-type tau, the mutant isoform appears diffuse throughout the cytoplasm; however, when mutant tau is expressed alone, it appears mostly bound to the microtubules. Dual imaging of the three- and four-repeat tau isoforms indicated that the expression of four-repeat tau displaced three-repeat tau from the microtubules. These results suggest that altered kinetic competition among the isoforms for microtubule binding could be a disease precipitant.
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PMID:Competition for microtubule-binding with dual expression of tau missense and splice isoforms. 1116 Aug 31

Some forms of genetically inherited dementia, including frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in tau. We have examined several mutations in the microtubule-binding portion of tau for their effect on microtubule binding, cellular distribution and cytoskeletal structure in mammalian cells. Using constructs coding for mutant (P301L and V337M) and wildtype human tau fused to a green fluorescent protein analog (EGFP) we followed the disposition of tau in live cells after transient transfection using confocal microscopy. Most of the tau protein localized to structures that resembled microtubules or microtubule bundles and co-localized with tubulin. At 3 days post-transfection mutant tau proteins showed a higher abundance of free tau in the cytoplasm than did wildtype tau. Cells expressing the P301L mutation showed proportionally more cytoplasmic localization of tau. Confirming these results, fractionated cells with mutant tau had a higher percentage of tau in the cytoplasmic compartment as compared to the cytoskeletal compartment. Cells with wildtype tau had most tau in the cytoskeletal fraction. Because the mutations (V337M, P301L) are associated with genetic tauopathies, these results suggest that a factor in disease etiology of genetic tauopathies and other dementias with altered tau is a greater abundance of tau in the cytoplasm due to decreased binding to microtubules. This increased cytoplasmic presence may be a significant factor in promoting tau aggregation.
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PMID:Mutated tau binds less avidly to microtubules than wildtype tau in living cells. 1117 Jan 76

Cumulative evidence suggests that neural network formation requires an ingenious regulation of the attractive and repulsive responses of growing axons to guidance cues. We examined the role of intracellular protein kinase A (PKA) signaling in the axonal pathfinding of olfactory sensory neurons in transparent zebrafish embryos. Microinjection of an olfactory marker protein gene promoter-driven double-cassette vector directed the expression of both the dominant form of PKA and green fluorescent protein fused with the microtubule-associated protein tau in the same olfactory neurons. The dominant-negative form of PKA enhanced the turning of olfactory neuron axons in the olfactory placode, whereas the disturbance effect of the constitutively active form on the axonal pathfinding was prominent in the olfactory bulb. Consistently, forskolin treatment severely inhibited the axonal extension in the olfactory bulb, but not in the olfactory placode. These results suggest that the switching of PKA signaling in developing olfactory sensory neurons is important for axonal pathfinding through the boundary between the olfactory placode and the olfactory bulb in vivo. We thus propose that the regulation of PKA signaling plays a key role in the long-distance axonal pathfinding through intermediate guideposts.
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PMID:Regulation by protein kinase A switching of axonal pathfinding of zebrafish olfactory sensory neurons through the olfactory placode-olfactory bulb boundary. 1207 93

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

Neurofibrillary tangles composed of hyperphosphorylated and aberrantly cleaved microtubule-associated protein tau are a major neuropathological hallmark of Alzheimer's disease. Recent studies suggest that the predominant neurotoxic effect of pathologically processed tau is mediated by intermediate tau multimers rather than the mature tau tangles, thus underscoring the importance of studying tau self-association preceding tangle formation. However, experimental approaches for such studies are limited. Here, we describe a modification of the beta-galactosidase (beta-gal) complementation assay, which provides a simple, sensitive and quantitative system to monitor pre-tangle tau-tau interactions in a cell model. Full-length tau (T4) and tau truncated at D421 (C3, to mimic caspase-cleaved tau) were fused to one of a pair of weakly complementing beta-gal mutants (Deltaalpha and Deltaomega) and expressed in human embryonic kidney cells. The tau-tau interactions and the subsequent juxtapositioning of Deltaalpha and Deltaomega led to beta-gal complementation and an increase in beta-gal activity which was detected by histochemical staining and quantified by chemiluminescent assays. After cross-linking with disuccinimidyl suberate, tau formed high molecular weight complexes which were detected on denaturing acrylamide gels, further confirming the close proximity among self-associated tau molecules. The self-association of C3 appeared to be less efficient than that of T4. Furthermore, treatment with lithium decreased beta-gal complementation of both T4 and C3 indicating that the interaction of these proteins was attenuated. Overall, this study suggests that beta-gal complementation assay can be a useful tool to monitor tau self-association.
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PMID:New application of beta-galactosidase complementation to monitor tau self-association. 1849 42

NAP (NAPVSIPQ) provides broad neuroprotection through microtubule interaction. Here, NAP was investigated for neuroprotection in an in vivo tauopathy model. Transgenic mice (2-month-old) that express the human double mutant tau protein [P301S;K257T] fused to the tau promoter, were subjected to daily intranasal drug treatment for approximately 5 months. Results showed increased performance in the NAP-treated mice compared to controls, as demonstrated in the Morris water maze, (p<0.05). Treatment continued for 5 additional months and mouse cortices were biochemically analyzed. Protein extraction identified increased tau protein content in the heat-stable soluble fraction, which contains microtubule-associated tau, in the 1-year-old NAP-treated mice as compared to vehicle-controls. Tau phosphorylation (Ser 202) increased in the tau-transgenic mice compared to control mice, and was significantly reduced in NAP-treated mice. The current studies show for the first time activity for NAP in a "pure" tauopathy model, positioning it as a promising drug candidate in multiple neurodegenerative tauopathies.
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PMID:NAP protects memory, increases soluble tau and reduces tau hyperphosphorylation in a tauopathy model. 1926 30

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.
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PMID:A new subtype of frontotemporal lobar degeneration with FUS pathology. 2069 41

We evaluated the potential of CE to analyse different isoforms of unphosphorylated recombinant tau protein and for separating one phosphorylated tau from the respective unphosphorylated protein. Different capillary coatings such as polyacrylamide, poly-(ethylene oxide) and polybrene (PB) were evaluated to overcome the poor efficiencies obtained with fused-silica capillary. Although peak asymmetry values were quite similar for the three investigated coatings, the peak efficiencies were 35-fold and 5-fold higher with PB coating than with polyacrylamide and poly(ethylene oxide) coatings, respectively. The recovery percentage (over 97%) was satisfactory and confirmed the efficacy of PB coating to limit the adsorption of tau protein to capillary walls. Moreover, PB coating produced higher repeatability for migration times (RSD values <1.2%) in comparison to the neutral coatings. The potential of PB-modified capillary in producing high resolutive separations of one phosphorylated tau isoform from its unphosphorylated counterpart and of a mixture of phosphorylated and unphosphorylated tau peptides was demonstrated with 50 mM phosphate buffer pH 3.0. The separation of unphosphorylated tau isoform 352 (Tau-352) from Tau-352 phosphorylated in vitro by the mitogen-activated protein kinase ERK2, was accomplished in less than 15 min.
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PMID:A quantitative CE method to analyse tau protein isoforms using coated fused silica capillaries. 2018 30

Frontotemporal lobar degeneration (FTLD) is a clinical syndrome characterized by behavioral and language difficulties, which refers to a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative disorders. Familial FTLD has been linked to mutations in several genes: the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B), and genetic locus on chromosome 9p linked to familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The associated neuropathology is characterized by selective degeneration of the frontal and temporal lobes with the neuronal and/or glial inclusions. The current classification of FTLD neuropathology is based on the major constituent protein of them: tau, TAR DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS). Abnormal phosphorylation, ubiquitination, and proteolytic cleavage are the common pathologic signature of tau and TDP-43 accumulated in diseased brains. Recent findings of TDP-43 and FUS reveal that FTLD and ALS share a common mechanism of pathogenesis. This review focuses on the current understanding of the molecular neuropathology of FTLD, and their relevance to the development of the therapeutics.
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PMID:[The molecular pathology of frontotemporal lobar degeneration]. 2049 55

A primary pathological hallmark of Alzheimer disease brain is the presence of neurofibrillary tangles, which are highly aggregated and insoluble accumulations of the microtubule-associated protein tau. Although it is becoming increasingly apparent that the mature neurofibrillary tangles are not the toxic species, intermediates between soluble tau and the neurofibrillary tangles likely play key roles in the neurodegenerative process. Therefore, it is critically important to be able to quantitatively monitor the process of tau aggregation in living cells in order to understand the evolution of tau from its physiological to its pathological forms. To detect and quantitate the aggregation of tau in cells, we established a split green fluorescent protein (GFP) complementation assay. In this assay, GFP is separated into two spontaneously associating fragments that form the fluorescent fluorophore. The smaller GFP fragment, GFP(11), is fused to tau and coexpressed in cells with the larger fragment GFP(1-10) leading to the association and reconstitution of the active fluorophore. However, if tau becomes partitioned into aggregates, the GFP(11) tag will be less accessible for interactions with GFP(1-10) resulting in a decrease in GFP complementation and fluorescence which can be monitored either using fluorescence microscopy or with a fluorescence plate reader. Thus, this assay is a valuable tool for measuring tau aggregation in living cells and evaluating -factors that modulate this process.
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PMID:Split GFP complementation assay for quantitative measurement of tau aggregation in situ. 2096 87


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