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)

A 46-year-old woman was admitted to our hospital for examination of her amnesia. Psychiatric examinations revealed that her recent memory was moderately disturbed despite well-preserved general cognitive function. Brain MRI and I-IMP SPECT (eZIS) revealed mild brain atrophy and hypoperfusion localized to the hippocampus, superior parietal lobule, and posterior cingulate gyrus. She was diagnosed with amnestic MCI at that time. However, five years later, she developed personality changes, parkinsonism and dementia. Investigation of her family medical history revealed that the patient's two sisters are demented and under the medical care. DNA analysis revealed an intronic mutation IVS10 C>T in the MAPT gene. Although her two sisters also have the same mutation, her elder sister has typical FTD without parkinsonism. Approximately 10% of patients with amnestic MCI develop Alzheimer's disease each year. Thus, amnestic MCI has been usually considered to be an early stage of Alzheimer's disease. Interestingly our patient having a MAPT gene mutation started to develop amnestic MCI as an initial symptom. Therefore because of the diversity in early clinical features of FTDP-17, aggressive DNA analysis is necessary for accurate diagnosis.
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PMID:[FTDP-17 presenting amnestic MCI as an initial symptom: case report]. 2235 29

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.
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PMID:Tau alternative splicing in familial and sporadic tauopathies. 2281 15

Characteristic tau isoform composition of the insoluble fibrillar tau inclusions define tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia with parkinsonism linked to chromosome 17/frontotemporal lobar degeneration-tau (FTDP-17/FTLD-tau). Exon 10 splicing mutations in the tau gene, MAPT, in familial FTDP-17 cause elevation of tau isoforms with four microtubule-binding repeat domains (4R-tau) compared to those with three repeats (3R-tau). On the basis of two well-characterised monoclonal antibodies against 3R- and 4R-tau, we developed novel, sensitive immuno-PCR assays for measuring the trace amounts of these isoforms in CSF. This was with the aim of assessing if CSF tau isoform changes reflect the pathological changes in tau isoform homeostasis in the degenerative brain and if these would be relevant for differential clinical diagnosis. Initial analysis of clinical CSF samples of PSP (n = 46), corticobasal syndrome (CBS; n = 22), AD (n = 11), Parkinson's disease with dementia (PDD; n = 16) and 35 controls revealed selective decreases of immunoreactive 4R-tau in CSF of PSP and AD patients compared with controls, and lower 4R-tau levels in AD compared with PDD. These decreases could be related to the disease-specific conformational masking of the RD4-binding epitope because of abnormal folding and/or aggregation of the 4R-tau isoforms in tauopathies or increased sequestration of the 4R-tau isoforms in brain tau pathology.
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PMID:Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies. 2299 75

Frontotemporal lobar degeneration (FTLD) describes a spectrum of clinically, pathologically and genetically heterogeneous neurodegenerative disorders of unknown aetiology. FTLD spectrum disorders collectively represent a leading cause of early-onset dementia, with most cases presenting between 45 and 64 years of age. FTLD is characterized by progressive changes in behaviour, executive dysfunction and/or language impairment and can be differentiated clinically into three frontotemporal dementia (FTD) syndromes as follows: (i) behavioural variant (bvFTD); (ii) semantic dementia (SD); and (iii) progressive nonfluent aphasia (PNFA). Additionally, there is a significant clinical, pathological and genetic overlap between FTD and motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) and the atypical parkinsonian syndromes, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). bvFTD is characterized by progressive behavioural impairment and a decline in executive function with frontal lobe-predominant atrophy, SD by a loss of object knowledge with prominent anomia and asymmetrical atrophy of the anterior temporal lobes and PNFA by expressive or motor speech deficits with predominantly left peri-sylvian atrophy. Recent advances in molecular biology and immunohistochemical staining techniques have further classified the FTLD spectrum disorders based upon the predominant neuropathological protein into three main categories: (i) microtubule-associated protein tau (FTLD-TAU); (ii) TAR DNA-binding protein-43 (FTLD-TDP); and (iii) fused in sarcoma protein (FTLD-FUS). Up to 40% of FTD patients report a family history of neurodegenerative illness, and one-third to one-half of familial cases of FTD follow an autosomal dominant inheritance pattern. Mutations in MAPT, PGRN, TARDBP, VCP and CHMP2B have been described, along with a recently identified C9ORF72 hexanucleotide repeat expansion. To date, there are no US FDA-approved treatments or disease-modifying therapies for FTD. Pharmacological strategies have focused on neurotransmitter replacement and modulation for the treatment of behavioural, motor and cognitive symptoms of FTD, and include selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, acetylcholinesterase inhibitors and glutamate NMDA receptor antagonists. At present, adequate management of FTD symptoms involves a combination of pharmacological therapy with behavioural, physical and environmental modification techniques.
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PMID:Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management. 2295 Apr 90

FTDP-17 mutations in the tau gene lead to early onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased levels of aggregation, hyperphosphorylation, defects in mRNA splicing, and weakened interaction with microtubules. Given the differential effects of the mutations, it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule stabilization ability of tau, while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems.
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PMID:FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. 2304 92

To elucidate involvement of tau protein in neurodegenerative processes in Alzheimer disease and related disorders, self-assembly process and degradative process of tau protein were examined. To understand the mechanisms of the aggregation, binding affinity of tau protein to 14-3-3 protein, which converts tau to a filamentous or aggregated form. was investigated employing a surface plasmon resonance assay. Phosphorylation of tau by protein kinase A increased affinity of tau to 14-3-3, whereas the phosphorylation attenuated formation of filaments or aggregates. FTDP-17 mutation increased affinity of unphosphorlated tau to 14-3-3, compared to wild typed unphosphorylated tau. However the phosphorylation increased its affinity further to the similar level of the affinity of phosphorylated wild typed tau. Similarly the phosphorylation also attenuated formation of filaments or aggreeagates from FTDP-17 mutated tau. To understand the mechanisms of the intracellular accumulation, possible involvement of proteases were studied. Among several proteases, puromycin-sensitive aminopeptidase (PSA) was found as a predominant regulator of degradation of tau protein. In addition FTDP-17 mutation increased phosphorylation of tau proten in cells, and attenuated intracellular degradation of tau protein. These results suggest that self-assembly and accumulation of tau protein are regulated by phosphorylation, and FTDP-17 mutation affects those complexed processes.
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PMID:[Alzheimer disease and tau protein]. 2319 53

Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.
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PMID:Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing. 2345 33

We have recently shown acetylation of tau at lysine residue 280 (AC-K280) to be a disease-specific modification in Alzheimer disease (AD), corticobasal degeneration, and progressive supranuclear palsy, likely representing a major regulatory tau modification. Herein, we extend our observations using IHC with a polyclonal antibody specific for AC-K280. Thirty brain regions were examined in argyrophilic grain disease (AGD; n = 5), tangle-predominant senile dementia (TPSD; n = 5), Pick disease (n = 4), familial AD (FAD; n = 2; PSEN1 p.G206A and p.S170P), and frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17; n = 2; MAPT p.P301L and IVS10 + 16). All AGD, TPSD, FAD, and FTDP-17 cases had significant AC-K280 reactivity that was similar in severity and distribution to phosphorylated tau. AC-K280 robustly labeled grain pathological characteristics in AGD and was predominantly associated with thioflavin-S-positive neurofibrillary tangles and less reactive in neuropil threads and extracellular tangles in TPSD and FAD. Thioflavin-S-negative neuronal and glial inclusions of patients with FTDP-17 were robustly AC-K280 reactive. A low degree of AC-K280 was found in a subset of 4-repeat tau-containing lesions in Pick disease. AC-K280 is a prominent feature of both neuronal and glial tau aggregations in tauopathies of various etiologies. The close association of AC-K280 with amyloid and pre-amyloid conformations of tau suggests a potential role in tangle maturation and, thus, could serve as a useful biomarker or therapeutic target in a variety of tauopathies.
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PMID:Acetylated tau neuropathology in sporadic and hereditary tauopathies. 2388 14

A key characteristic of Alzheimer's disease and other tauopathies is the progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. In the present study, we use transgenic Drosophila melanogaster as a model to analyze in vivo the effect of expressing pseudophosphorylated tau (S199E/T212E/T231E/S262E tau) on pathological human tau (PH-tau) and on the FTDP-17 mutant R406W (PH-tauR406W). We used two different inducers that produced different levels of tau expression. The expression of these forms of tau did not significantly affect the lifespan of the flies. Flies expressing PH-tau displayed a clear locomotor dysfunction compared to those expressing normal tau regardless of the level of expression. At lower level of expression, this pathological phenotype was found to be age-dependent. At 35 days old, PH-tau flies showed the strongest locomotor impairment compare to flies expressing human tau or control flies (46%, 18% and 18% of flies remained on the bottom of the vials, respectively). At higher levels of expression, PH-tau flies showed these defects at seven days of age and the dysfunction also became significant for flies expressing tauR406W and PH-tauR406W. Whole brain immunochemistry analysis revealed that PH-tau as well as PH-tauR406W appeared to have abnormal mushroom body structures, critical structures involved in olfactory learning and memory in Drosophila. Severe olfactory learning deficits were induced by the expression of PH-tau. Taken together, our findings demonstrate that PH-tau induced a toxic effect in Drosophila, as flies develop both an abnormal motor deficit, associated with disruption of the mushroom body neurons, and impaired olfactory learning.
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PMID:Expression of Alzheimer-like pathological human tau induces a behavioral motor and olfactory learning deficit in Drosophila melanogaster. 2394 1

Tau pre-mRNA contains a stem-loop structure involved in the regulation of the alternative splicing of tau protein. We describe here a new family of Tau RNA ligands selected by dynamic combinatorial chemistry based on the combination of ametantrone with small RNA-binding molecules. The most promising compound results from derivatization of one of the side chains of the anthraquinone ring with the small aminoglycoside neamine through a short spacer. This compound binds the RNA target with a high affinity in a preferred binding site, in which the heteroaromatic moiety intercalates in the bulged region of the stem-loop and its side chains and neamine interact with the major groove of the RNA. Importantly, binding of this compound to mutated RNA sequences involved in the onset of some tauopathies such as FTDP-17 restores their thermodynamic stability to a similar or even higher levels than that of the wild-type sequence, thereby revealing its potential as a modulator of Tau pre-mRNA splicing.
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PMID:Ametantrone-based compounds as potential regulators of Tau pre-mRNA alternative splicing. 2537 55


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