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)

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. In patients diagnosed with frontotemporal dementia and parkinsonism linked to chromosome 17, mutations in the gene encoding tau (MAPT) have been identified that disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau. Abnormal filamentous tau deposits have been reported as a pathological characteristic in several other neurodegenerative diseases, including frontotemporal dementia, Pick Disease, Alzheimer disease, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration. In the last five years, extensive research has identified 34 different pathogenic MAPT mutations in 101 families worldwide. In vitro, cell-free and transfected cell studies have provided valuable information on tau dysfunction and transgenic mice carrying human MAPT mutations are being generated to study the influence of MAPT mutations in vivo. This mutation update describes the considerable differences in clinical and pathological presentation of patients with MAPT mutations and summarizes the effect of the different mutations on tau functioning. In addition, the role of tau as a genetic susceptibility factor is discussed, together with the genetic evidence for additional causal genes for tau-positive as well as tau-negative dementia.
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PMID:The role of tau (MAPT) in frontotemporal dementia and related tauopathies. 1536 85

Filamentous tau-positive inclusions in neurons and glia are a unifying mechanism underlying a variety of late onset neurodegenerative disorders termed "tauopathies". Oligodendroglial lesions and white matter pathology have long been underestimated and are specifically prominent in frontotemporal dementias (FTDs), such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Oligodendrocytes contain an extensive microtubule network and express the microtubule-associated protein tau. Tau-positive inclusion bodies in oligodendrocytes are positively stained with antibodies against ubiquitin and heat shock proteins (HSPs). Specifically the small HSP alphaB-crystallin has been identified in oligodendroglial lesions. HSPs act as molecular chaperones and prevent the accumulation of abnormal proteins, and support proteolytic degradation by targeting non-reparable proteins to the ubiquitin proteasomal pathway. HSPs and the proteasomal system closely work together. The present report summarizes recent data on HSP induction and aggregate formation in oligodendroglia cell culture systems, indicating that posttranslational modification of tau, HSP induction and alterations of the proteasomal system, which might occur during aging and disease processes, are involved in the neuropathological events leading to aggregate formation and degeneration.
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PMID:Tau-inclusion body formation in oligodendroglia: the role of stress proteins and proteasome inhibition. 1546 74

Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.
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PMID:The cytoskeleton in neurodegenerative diseases. 1549 40

In the central nervous system (CNS), aberrant changes in tau mRNA splicing and consequently in protein isoform ratios cause abnormal aggregation of tau and neurodegeneration. Pathological tau causes neuronal loss in Alzheimer's disease (AD) and a diverse group of disorders called the frontotemporal dementias (FTD), which are two of the most common forms of dementia and afflict more than 10% of the elderly population. Autosomal dominant mutations in the tau gene cause frontotemporal dementia with parkinsonism-chromosome 17 type (FTDP-17). Just over half the mutations affect tau protein function and decrease its affinity for microtubules (MTs) or increase self-aggregation. The remaining mutations occur within exon 10 (E10) and intron 10 sequences and alter complex regulation of E10 splicing by multiple mechanisms. FTDP-17 splicing mutations disturb the normally balanced levels of distinct protein isoforms that result in altered biochemical and structural properties of tau. In addition to FTDP-17, altered tau isoform levels are also pathogenically associated with other FTD disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration and Pick's disease; however, the mechanisms remain undefined and mutations in tau have not been detected. FTDP-17 highlights the association between splicing mutations and the pronounced variability in pathology as well as phenotype that is characteristic of inherited disorders.
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PMID:Regulation of tau isoform expression and dementia. 1561 30

Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases. They include the largely sporadic Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, Pick's disease and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). For a long time, it was unclear whether the dysfunction of tau protein follows disease or whether disease follows tau dysfunction. This was resolved when mutations in Tau were found to cause FTDP-17. Currently, 32 different mutations have been identified in over 100 families. About half of the known mutations have their primary effect at the protein level. They reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level and perturb the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in a relative overproduction of tau protein with four microtubule-binding domains in the brain. Individual Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration or Pick's disease. Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration. At a practical level, the new work is leading to the production of experimental animal models that reproduce the essential molecular and cellular features of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and nerve cell degeneration.
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PMID:Mutations causing neurodegenerative tauopathies. 1561 42

Argyrophilic grain disease (AgD) is a late-onset dementia morphologically characterized by the presence of abundant spindle-shaped argyrophilic grains (ArG) in neuronal processes and coiled bodies in oligodendrocytes. AgD changes consist of the microtubule-associated protein tau in an abnormally and hyperphosphorylated state and are mainly found in limbic regions, for example, in the hippocampus, the entorhinal and transentorhinal cortices and the amygdala. AgD shows a significant correlation with advancing age, and it became apparent from recent clinicopathological studies that it might account for approximately 5% of all dementia cases. Further immunohistochemical and biochemical studies revealed that AgD is a four-repeat (4R) tauopathy similar to PSP and corticobasal degeneration (CBD), but distinct from Alzheimer's disease (AD) and Pick's disease. Moreover, a common genetic background regarding the tau gene haplotype has been suggested for AgD, PSP and CBD. However, although there are currently only limited data available, AgD seems to be clinically distinct from PSP and CBD and shares rather features of (mild) AD or other forms of 'limbic' dementias, among them senile dementia with tangles and the localized form of AD.
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PMID:Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. 1564 85

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.
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PMID:Cholinergic systems in progressive supranuclear palsy. 1564 52

The term of the frontotemporal dementia was first proposed by Lund and Manchester group in 1994, but the definition of frontotemporal dementia has been still controversial. Frontotemporal dementia is caused by several diseases which have fronto-temporal atrophy. The diseases are collectedly designated as frontotempoal degeneration. The frontotemporal degeneration encompasses several diseases such as Pick disease (frontotemporal degeneration with Pick bodies) and frontotemporal degeneration with ubiquitin-positive inclusions and frontotemporal degeneration (no inclusion bodies are observed). Pick bodies are consisted of abnormally phosphorylated tau protein. The recent discoveries of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) suggest important role of tau abnormalities in the disease mechanism. The frontotemporal degeneration has also another clinical phenotype such as slowly progressive aphasia. Slowly progressive aphasia has subtypes of non-fluent aphasia and semantic aphasia. Some patients with corticobasal degeneration or progressive supranuclear palsy also reveal the clinical pictures of frontotemporal dementia or slowly progressive aphasia and should be considered as differential diagnosis in the patients with frontotemporal dementia or slowy progressive aphasia.
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PMID:[Frontotemporal dementia and frontotemporal degeneration--how to define?]. 1565 18

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a group of hereditary, adult-onset, progressive neurodegenerative syndromes, which lead to the accumulation of intracellular deposits of hyperphosphorylated tau protein. Since the original definition of FTDP-17 in the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 80 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 35 different mutations outside and on exon 10 of tau gene. The symptomatic onset of FTDP-17 is usually insidious. The clinical phenotypes are characterized by behavioral, cognitive and motor disturbances that may occur in various combinations and in varying degrees of severity. Affected individuals develop a constellation of signs, including at least two of the three cardinal manifestations of FTDP-17. It should be noted that there is significant clinical phenotypic heterogeneity in individuals with different mutations. In addition, interfamilial and intrafamilial variability of clinical phenotype is often seen among individuals carrying the same mutation. Macroscopically, the degree of brain atrophy observed varies with a brain weight ranging from approximately 825 to 1,290 grams. In the advanced stages, the degree of atrophy varies and may be present in the frontal and temporal lobes, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus and ventral hypothalamus. Microscopically, the neuropathologic hallmark is the presence of tau protein deposits in neurons or in both neurons and glia. The cellular pathology of the neuron may resemble that of Alzheimer disease (AD) or Pick disease for the presence of neurofibrillary tangles or Pick bodies. The cellular pathology of glial cells may resemble that of progressive supranuclear palsy or corticobasal degeneration for the presence of coiled bodies in oligodendroglial cells, tufted astrocytes or astrocytic plaques. Mutations in exons 1, 10 and intron following exon 10 are associated with neuronal and glial tau deposition. Mutations in exons 9, 11, 12 and 13 lead to deposits of tau filaments predominantly in neurons.
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PMID:[Clinical, genetic and pathological aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)]. 1565 19

The microtubule-associated protein tau is highly soluble under physiological conditions. However, in tauopathies, tau protein aggregates into insoluble filaments and neurofibrillary tangles (NFTs). The mechanisms underlying the formation of tau filaments and NFTs in tauopathies remain unclear. Several lines of evidence suggest that transglutaminase may cross-link tau into stable, insoluble aggregates, leading to the formation of NFTs in Alzheimer's disease and progressive supranuclear palsy. To further determine the contribution of transglutaminase in the formation of NFTs, we compared the levels of cross-linked tau protein from P301L tau transgenic mice that develop NFTs to four-repeat wild-type (4RWT) tau transgenic and nontransgenic mice that do not develop NFT pathology. Immunoprecipitation and immunoblotting experiments show that transglutaminase cross-links phosphorylated tau in the hindbrain of P301L tau transgenic mice but not in mice overexpressing 4RWT tau and nontransgenic mice. Cross-linked, phosphorylated tau from P301L tau transgenic mice runs as high-molecular mass aggregates on Western blots, similar to cross-linked tau from paired helical filaments of Alzheimer's disease. We also used double-label immunofluorescence to demonstrate colocalization of PHF-1-immunoreactive tau and the transglutaminase-catalyzed cross-link in the hindbrain, spinal cord, and cortex of P301L tau transgenic mice. In the spinal cord, 87% of PHF-1-labeled cells colocalize with the transglutaminase-catalyzed cross-link. Additionally, transglutaminase enzymatic activity is significantly elevated in the spinal cord of P301L tau transgenic mice. These studies further implicate transglutaminase in the formation and/or stabilization of NFT and paired helical filaments and provide a model system to investigate the therapeutic potential of transglutaminase inhibitors in tauopathies.
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PMID:Tau protein is cross-linked by transglutaminase in P301L tau transgenic mice. 1568 60


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