Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau are a characteristic pathological observation in several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. The recent finding that mutations in the tau gene are responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided convincing evidence that tau protein plays a key role in neurodegeneration. In the short period since the identification of pathogenic mutations in tau, remarkable progress has been made in understanding some of the mechanisms by which these mutations lead to neurodegeneration. Understanding the disease processes will hopefully provide us with new leads in developing effective therapies for dementia.
Hum Mol Genet 2000 Apr 12
PMID:Untangling tau-related dementia. 1076 21

Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases.
Mol Cell Biol 2000 Jun
PMID:Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. 1080 46

The microtubule-associated protein tau is a member of a group of proteins, promoting assembly and stabilization of microtubules. In several tauopathic neurodegenerative disorders, namely Alzheimer's and Pick's disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP 17) this protein is converted into fibrilar polymers which form the component of insoluble proteanous deposits such as neurofibrillary tangles. The formation of these fibrils is believed to interrupt the physiological function of neurons resulting in degeneration and cell death. Tau protein exists as a family of heterogeneous isoforms derived by both, differential splicing of tau-mRNA and posttranslational modification of the protein. Since the role of the different isoforms during the process of neurodegeneration is not well understood and as their balance might be altered in some cases of tauopathies (Spillantini et al., Proc. Natl. Acad. Sci. USA 1998;95:7737-7741), the detailed analysis of the molecular heterogeneity gained outstanding interest. The method presented here allows the analysis of both, differential splicing and phosphorylation of tau protein by the application of two-dimensional (2D) electrophoresis and Western blot detection. Tau protein isoforms could be identified from the 2D pattern of dephosphorylated tau in concordance with the results of tau-mRNA analysis by RT-PCR. The protocol presented was successfully applied to analysis of tau isoforms of human brain (Janke et al., FEBS Lett. 1996;379:222-226) and of several species, revealing a phylogenetic correlation of tau protein patterns in mammals (Janke et al., Mol. Brain Res. 1999;68:119-128). The present paper provides a detailed description of the technique and discusses its prospects and limits.
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PMID:Analysis of the molecular heterogeneity of the microtubule-associated protein tau by two-dimensional electrophoresis and RT-PCR. 1090 88

Multiple tau gene mutations are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with filamentous tau aggregates as the major lesions in the CNS of these patients. Recent studies have shown that bacterially expressed recombinant tau proteins with FTDP-17 missense mutations cause functional impairments, i.e., a reduced ability of mutant tau to bind to or promote the assembly of microtubules. To investigate the biological consequences of FTDP-17 tau mutants and assess their ability to form filamentous aggregates, we engineered Chinese hamster ovary cell lines to stably express tau harboring one or several different FTDP-17 mutations and showed that different tau mutants produced distinct pathological phenotypes. For example, delta K, but not several other single tau mutants (e.g., V337 M, P301L, R406W), developed insoluble amorphous and fibrillar aggregates, whereas a triple tau mutant (VPR) containing V337M, P301L, and R406W substitutions also formed similar aggregates. Furthermore, the aggregates increased in size over time in culture. Significantly, the formation of aggregated delta K and VPR tau protein correlated with reduced affinity of these mutants to bind microtubules. Reduced phosphorylation and altered proteolysis was also observed in R406W and delta K tau mutants. Thus, distinct pathological phenotypes, including the formation of insoluble filamentous tau aggregates, result from the expression of different FTDP-17 tau mutants in transfected Chinese hamster ovary cells and implies that these missense mutations cause diverse neurodegenerative FTDP-17 syndromes by multiple mechanisms.
Mol Biol Cell 2000 Dec
PMID:Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells. 1110 10

Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.
Hum Mol Genet 2000 Dec 12
PMID:Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients. 1111 52

The phosphatidylinositol (PI)-3 kinase-Akt/PKB survival pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective effect against neurotoxins that produce oxidative stress and neurodegeneration has not been investigated. We analyzed the effect of this pathway on the action of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Overexpression of a membrane-targeted, N-myristylated fusion protein of enhanced green fluorescence protein (EGFP) and mouse Akt1 attenuated the apoptotic effect of the neurotoxin in PC12 cells. This effect was not due to protection of mitochondrial complex I activity or restoration of energy charge. Following MPP+-treatment, myr-EGFP-Akt1-transfected cells exhibited an unaltered mitochondrial membrane potential and lower ROS levels than control cells. These results provide a new site of action of Akt/PKB at the level of the oxidative detoxifying cell machinery and suggest that this effect may be responsible in part for the resistance of myr-EGFP-Akt1-expressing cells to oxidative stress and MPP+-induced apoptosis.
Mol Cell Neurosci 2001 Jan
PMID:Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals. 1116 70

Depression is the most prevalent functional psychiatric disorder in late life. The problem of motor disorders associated with antidepressant use is relevant in the elderly. Elderly people are physically more frail and more likely to be suffering from physical illness, and any drug given may exacerbate pre-existing diseases, or interact with other drug treatments being administered for physical conditions. Antidepressants have been reported to induce extrapyramidal symptoms, including parkinsonism. These observations prompted us to review the neurobiological mechanism that may be involved in this complex interplay including neurotransmitters and neuronal circuits involved in movement and emotion control and their changes related to aging and disease. The study of the correlations between motor and mood disorders and their putative biochemical bases, as presented in this review, provide a rationale either to understand or to foresee motor side effects for psychotropic drugs, in particular antidepressants.
Mol Psychiatry 2001 Mar
PMID:Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly. 1131 14

Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.
Mol Cell Neurosci 2001 Jul
PMID:Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. 1146 Nov 55

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.
Mol Cell Biol 2001 Aug
PMID:Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism. 1146 16

Early-onset parkinsonism (EOP) may be associated with different mutations in the parkin gene, including exon deletions and duplications. To test for gene dosage alterations, we developed a new method of quantitative duplex PCR using the fluorescence resonance energy transfer technique on the LightCycler (Roche Diagnostics). In 21 patients with EOP, three mutations (a single base pair substitution in exon 3 and small deletions in exon 9) were detected by conventional mutational screening (single-strand conformation polymorphism and sequence analysis), while alterations of gene dosage were found in seven patients. We identified heterozygous and compound heterozygous deletions of exons 2, 3, 5 and 7. The latter was also found in the homozygous state. In addition, two heterozygous duplications of exon 4 were observed. Remarkably, two patients carried more than two parkin mutations. This is the first study systematically screening all 12 exons of parkin by real-time, kinetic quantification and clearly shows that mutational analysis of the parkin gene should include gene dosage studies. Furthermore, our method of quantitative PCR is easily applicable to any other gene to be screened for deletions or duplications of whole exons.
Hum Mol Genet 2001 Aug 01
PMID:The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism. 1148 68


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