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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interest in the microtubule-associated protein tau stems from its critical roles in neural development and maintenance, as well as its role in Alzheimer's, FTDP-17 and related neurodegenerative diseases. Under normal circumstances, tau performs its functions by binding to microtubules and powerfully regulating their stability and growing and shortening dynamics. On the other hand, genetic analyses have established a clear cause-and-effect relationship between tau dysfunction/mis-regulation and neuronal cell death and dementia in FTDP-17, but the molecular basis of tau's destructive action(s) remains poorly understood. One attractive model suggests that the intracellular accumulation of abnormal tau aggregates causes cell death, i.e., a gain-of-toxic function model. Here, we describe the evidence and arguments for an alternative loss-of-function model in which tau-mediated neuronal cell death is caused by the inability of affected cells to properly regulate their microtubule dynamic due to mis-regulation by tau. In support of this model, our recent data demonstrate that missense FTDP-17 mutations that alter amino acid residues near tau's microtubule binding region strikingly modify the ability of tau to modulate microtubule dynamics. Additional recent data from our labs support the notion that the same dysfunction occurs in the FTDP-17 regulatory mutations that alter tau RNA splicing patterns. Our model posits that the dynamics of microtubules in neuronal cells must be tightly regulated to enable them to carry out their diverse functions, and that microtubules that are either over-stabilized or under-stabilized, that is, outside an acceptable window of dynamic activity, lead to neurodegeneration. An especially attractive aspect of this model is that it readily accommodates both the structural and regulatory classes of FTDP-17 mutations.
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PMID:Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. 1561 45

A double transgenic mouse expressing the amyloid precursor protein, bearing the Swedish mutations, and expressing tau protein containing three of the mutations present in frontotemporal dementia linked to chromosome 17 (FTDP-17), has been characterized. In the double transgenic mouse an increase in tau phosphorylation at serine S262 and S422 was observed compared with that found in simple transgenic mice. The phosphorylation at S262 was also found, in a much lower level, in the single transgenic mouse expressing amyloid precursor protein (APP), and it was absent in that overexpressing tau variant. Additionally, in the double transgenic mouse a slight increase in the amount of sarkosyl insoluble tau polymers was observed in comparison with that found in single transgenic tau mouse. Also, wider tau filaments were found in the double transgenic mouse compared with those found in the single transgenic mouse. Our results suggest that beta-amyloid peptide could facilitate the phosphorylation of tau at a site not directed by proline, such as serine 262, and that modification could facilitate tau aberrant aggregation. Also, they suggest that different types of tau filamentous polymers can occur in different mouse models for tauopathies, like those used for Alzheimer's disease or FTDP-17.
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PMID:Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. 1566 90

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.
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PMID:Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. 1583 1

Familial frontotemporal dementia (FTD), characterized by tau-negative, ubiquitin-positive inclusions at autopsy, is linked to a chromosomal region at 17q21 (FTDU-17), encompassing the gene encoding the microtubule associated protein tau, MAPT. Mutations in MAPT were previously identified in familial FTD with parkinsonism (FTDP-17); however, in FTDU-17 patients, no pathogenic mutations were found in exonic regions consistent with the lack of tauopathy in FTDU-17 brains. Here, we excluded mutations in MAPT by genomic sequencing of 138.5 kb in FTDU-17 patients. Next, to facilitate the identification of the actual underlying genetic defect, we assembled the 6.5 Mb FTDU-17 sequence. Annotation demonstrated that MAPT is surrounded by three highly homologous low-copy repeats (LCRs) in a region of 1.7 Mb. Using evolutionary studies, short tandem repeat-based linkage disequilibrium (LD) and macro-restriction mapping, we demonstrated that these LCRs are at the basis of a series of rearrangements in the MAPT genomic region. One is an inversion that occurred 3 million years ago and resulted in a common polymorphism in humans to date. This inversion plus flanking LCRs spanned approximately 1.3 Mb and was shown to underlie the extended LD and haplotypes H1 and H2 across MAPT. However, in the FTDU-17 families, we ascertained segregation analysis precluding a relationship between the FTDU-17 and the H1/H2 inversion. The presence of multiple homologous LCRs in the region predicts that other potentially more complex genomic rearrangements might be underlying FTDU-17.
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PMID:Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. 1588 85

A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.
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PMID:Quantitative analysis of tau isoform transcripts in sporadic tauopathies. 1595 Jul 67

Genetic factors are involved in the aetiology of dementias. Three genes have been identified which, when mutated, cause Familial Alzheimer disease (FAD): the presenilin-1 (PS1), the presenilin-2 (PS2) and the amyloid precursor protein (APP) genes. Together, these mutations are responsible for 30-50% of the cases with autosomal dominant Alzheimer disease (AD), and for about 5% of all AD cases. While over 130 mutations have been identified in PS1, mutations in PS2 and APP are rarer, since only 10 and 22 mutations, respectively, have been found in these FAD genes. Instead, mutations in the MAPT gene were associated with Familial Frontotemporal dementia (FFTD) linked to chromosome 17 (FTDP-17). Frontotemporal dementia (FTD) can occur in a sporadic form, but in 30-50% of cases there is a positive family history of dementia. In this study, we determined the spectrum of mutations and the relative contribution of the above mentioned four genes in our Italian clinical series of patients with a positive family history of dementia.
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PMID:Prevalence of pathogenic mutations in an Italian clinical series of patients with familial dementia. 1597 68

Mutations in the tau gene cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 characterized by filamentous tau protein deposits. Here we describe the clinical and neuropathological features of a case from a newly identified family with an intron 10+3-splice site mutation in the tau gene. The proband presented with severe personality changes and stereotyped speech followed by parkinsonian symptoms. He died at age 56 after a disease duration of approximately 6 years. At autopsy, there was marked frontotemporal degeneration with abundant tau-immunoreactive neuronal and glial inclusions widespread in the cortex and brainstem. RT-PCR analysis revealed a 3.7-fold increase of tau transcripts with exon 10, resulting in an 1.7-fold higher expression level of 4-repeat tau isoforms in soluble tau fractions when compared to control brains and exclusively 4-repeat tau isoforms in the sarcosyl-insoluble tau fractions. In accordance with the hypothesis that the overexpression leads to saturation of microtubule binding sites and an increase of unbound 4-repeat tau isoforms which assemble into filaments, the neuronal and glial inclusions in this case were exclusively composed of 4-repeat tau isoforms. The clinical and neuropathological data of this family are compared with results from the two other published families with the intron 10 + 3 mutation, the MSTD and the SOT 254 family.
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PMID:A new family with frontotemporal dementia with intronic 10+3 splice site mutation in the tau gene: neuropathology and molecular effects. 1600 20

Microtubule-associated protein tau is the major component of the neurofibrillary tangles of Alzheimer disease (AD) and is genetically linked to frontotemporal dementias (FTDP-17). We have recently shown that tau interacts with the SH3 domain of Fyn, an Src family non-receptor tyrosine kinase, and is tyrosine-phosphorylated by Fyn on Tyr-18. Also, tyrosine-phosphorylated tau is present in the neuropathology of AD. To determine whether alterations in the tau-Fyn interaction might correlate with disease-related factors in AD and FTDP-17, we have performed real-time surface plasmon resonance studies on a panel of 21 tau constructs with Fyn SH3. We report that the interaction between Fyn SH3 and 3R-tau was 20-fold higher than that with 4R-tau. In addition, the affinity between 4R-tau and Fyn SH3 was increased 25-45-fold by phosphorylation-mimicking mutations or by FTDP-17 mutations. In vitro kinase reactions show that tau, with lower affinity SH3 interactions, exhibited a lower level of Tyr-18 phosphorylation under our reaction conditions. Lastly, we have demonstrated that tau is phosphorylated on Tyr-18 in the tau P301L mouse model for tauopathy (JNPL3). In summary, our results suggest that disease-related phosphorylation and missense mutations of tau increase association of tau with Fyn. Because these effects are mediated through the 4R component of the tau population, these results also have implications for the FTDP-17 diseases caused by increased expression of 4R-tau. Our data support a role for the Fyn-tau interaction in neurodegeneration.
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PMID:Disease-related modifications in tau affect the interaction between Fyn and Tau. 1611 84

Formation of inclusions containing polymerized tau protein is a hallmark of Alzheimer's disease and related disorders. In vitro studies have demonstrated the ability of polyglycosaminoglycans and fatty acids to promote tau polymerization. In this report, we examined their impact on tau polymerization separately and together. Tau assembly with only arachidonic acid was faster than that with only heparin. The presence of dithiothreitol reduced heparin-promoted tau assembly while enhancing arachidonic acid reactions. However, simultaneous use of these molecules increased the rate of filament assembly substantially, negated the effects of the reducing agent, and has very little effect on the morphology of filaments. The increases in polymerization resulted from accelerated nucleation. Finally, a FTDP-17 mutation was identified that could complement heparin to generate assembly kinetics similar to that of wild-type tau with both inducers. Our results support a multiple-hit model where several induced changes in tau can function independently to promote tau assembly.
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PMID:Evidence for independent mechanisms and a multiple-hit model of tau assembly. 1632 69

Neurofibrillary tangles are brain lesions that have been discovered at the beginning of the 20th century, using histological silver staining. Tangles are intra-neuronal hallmarks of a degenerating process: neurofibrillary degeneration (NFD). The basic component involved in tangle formation is tau protein. Tangles are found in more than 20 different neurodegenerative disorders, suggesting that NFD is a unique consequence to different types of etiological factors. However, tangles have a morphological and biochemical signature which is disease-specific. They are made up of different types of filaments such as paired helical filaments (PHFs) in Alzheimer's disease or straight filaments in progressive supranuclear palsy. Tau aggregates have a disease-specific biochemical bar-code due to the aggregation of specific sets of tau isoforms. Tau lesions have also a disease-specific pattern of spatio-temporal progression in the human brain which is well correlated to cognitive impairment. At last, pathological tau mutations are at the origin of familial fronto-temporal diseases with parkinsonism (FTDP-17). Together, these observations have generated the concept of tauopathies. Indeed, each tauopathy is defined by a combination of clinical, neuropathological, biochemical and genetic features. Most of them have a specific defect on tau (mutation, aberrant splicing, abnormal phosphorylation, abnormal processing, neuronal or genotypic vulnerability), suggesting that, in fact, the etiology of most tauopathies is directly linked to tau dysfunction. In conclusion, we observe that most dementing disorders are tauopathies and that most demented patients have a tauopathy.
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PMID:Tauopathies: recent insights into old diseases. 1641 89


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