Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer's disease paired helical filaments. Previously, we reported that ABalphaC, the dominant brain isoform of protein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, and is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion mutants, we found that ABalphaC binds a domain on tau that is indistinguishable from its MT-binding domain. ABalphaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABalphaC and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these interactions differentially inhibit the ability of PP2A to dephosphorylate various substrates, including tau and tubulin. Finally, tubulin assembly decreases PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate how structural interactions among ABalphaC, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal interactions could contribute significantly to development of tauopathies such as Alzheimer's disease.
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PMID:Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. 1046 80

Within neurofibrillary tangles and dystrophic neurites of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In the present study, we examined the effect of okadaic acid (OA), a protein phosphatase inhibitor, in rat cultured neurons. Low concentrations of OA induce degeneration of neurites, rounding of cell bodies, detachment from the substratum, and eventual neuronal death. During OA-induced degeneration, SMI-31 immunoreactivity became punctate in neurites at 6 h after OA treatment, and over time, accumulated in cell bodies and dystrophic neurites. Hyperphosphorylation of tau and marked loss of MAP-2-positive dendrites occurred after 6 h of treatment with OA. Thereafter, AT-8 and PHF-1 immunoreactivity accumulated in cell bodies and subsequently appeared in distal axon-like neurites. These results demonstrate that OA treatment induced hyperphosphorylation of tau and preferential dendritic damage, with subsequent accumulation of phosphorylated tau in cell bodies and dystrophic axon-like neurites. OA-induced neurodegeneration may provide a useful model to study AD.
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PMID:Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment. 1051 48

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

Down syndrome is one of the major causes of mental retardation and congenital heart malformations. Other common clinical features of Down syndrome include gastrointestinal anomalies, immune system defects and Alzheimer's disease pathological and neurochemical changes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which must underlie the pathogenesis of the abnormalities that occur in Down syndrome. Here we show that DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B. The DSCR1 binding region in calcineurin A is located in the linker region between the calcineurin A catalytic domain and the calcineurin B binding domain, outside of other functional domains previously defined in calcineurin A. DSCR1 belongs to a family of evolutionarily conserved proteins with three members in humans: DSCR1, ZAKI-4 and DSCR1L2. We further demonstrate that overexpression of DSCR1 and ZAKI-4 inhibits calcineurin-dependent gene transcription through the inhibition of NF-AT translocation to the nucleus. Together, these results suggest that members of this newly described family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and as such, they may be involved in many physiological processes.
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PMID:DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. 1086 Dec 95

Abnormal tau-immunoreactive filaments are a hallmark of tauopathies, including Alzheimer's disease (AD). A higher phosphorylation ("hyperphosphorylation") state of tau protein may represent a critical event. To determine the potential role of tau hyperphosphorylation in these disorders, mutated tau proteins were produced where serine/threonine residues known to be highly phosphorylated in tau filaments isolated from AD patients were substituted for glutamate to simulate a paired helical filament (PHF)-like tau hyperphosphorylation. We demonstrate that, like hyperphosphorylation, glutamate substitutions induce compact structure elements and SDS-resistant conformational domains in tau protein. Hyperphosphorylation-mimicking glutamate-mutated tau proteins display a complete functional loss in its ability to promote microtubule nucleation which can partially be overcome by addition of the osmolyte trimethylamine N-oxide (TMAO), which is similar to phosphorylated tau. In addition, glutamate-mutated tau proteins fail to interact with the dominant brain protein phosphatase 2A isoform ABalphaC, and exhibit a reduced ability to assemble into filaments. Interestingly, wild-type tau and phosphorylation-mimicking tau similarly bind to microtubules when added alone, but the mutated tau is almost completely displaced from the microtubule surface by equimolar concentrations of wild-type tau. The data indicate that glutamate-mutated tau proteins provide a useful model for analyzing the functional consequences of tau hyperphosphorylation. They suggest that several mechanisms contribute to the abnormal tau accumulation observed during tauopathies, in particular a selective displacement of hyperphosphorylated tau from microtubules, a functional loss in promoting microtubule nucleation, and a failure to interact with phosphatases.
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PMID:Structural and functional implications of tau hyperphosphorylation: information from phosphorylation-mimicking mutated tau proteins. 1105 69

The authors discuss the importance that molecular medicine has assumed in recent years. Molecular methodologies have clearly demonstrated that immunological diversity is based fundamentally on the rearrangement of the genes encoding antigen B and T cell receptors. The importance of oncogenes, and their translocation in tumoral pathologies is emphasized, a case in point being the alterations observed in chronic myeloid leukemia and acute promyelocytic leukemia and their implication for innovative therapy. The importance of prothrombin and factor V genetic-molecular alterations in thromboembolic pathology and of the activation of calcineurin phosphatase or other intracellular signal regulator molecules during cardiac insufficiency genesis is also discussed. Particular attention is paid to progress regarding the socially important Alzheimer's syndrome, and the diagnosis of endocrine tumors. Moreover, the authors believe that the identification of new endocrine nuclear receptors, "orphans" of hormonal ligands, will open up interesting prospects--even therapeutic--in endocrinology. The authors conclude by reviewing the therapeutic prospects for immunodeficiency syndromes and malignant tumors, offered by new gene therapy methodologies. They also discuss recent results of studies on the aging process which, until not many years ago, appeared adventuristic. Today they are opening prospects of great interest.
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PMID:[Molecular medicine: new tools for better understanding and treatment of diseases in humans]. 1105 61

In Alzheimer disease brain the activities of protein phosphatase (PP)-2A and PP-1 are decreased and the microtubule-associated protein tau is abnormally hyperphosphorylated at several sites at serine/threonine. Employing rat forebrain slices kept metabolically active in oxygenated artificial CSF as a model system, we investigated the role of PP-2A/PP-1 in the regulation of some of the major abnormally hyperphosphorylated sites of tau and the protein kinases involved. Treatment of the brain slices with 1.0 microM okadaic acid inhibited approximately 65% of PP-2A and produced hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422. No significant changes in the activities of glycogen synthase kinase-3 (GSK-3) and cyclin dependent protein kinases cdk5 and cdc2 were observed. Calyculin A (0.1 microM) inhibited approximately 50% PP-1, approximately 20% PP-2A, 50% GSK-3 and approximately 30% cdk5 but neither inhibited the activity of cyclin AMP dependent protein kinase A (PKA) nor resulted in the hyperphosphorylation of tau at any of the above sites. Treatment of brain slices with 1 microM okadaic acid plus 0.1 microM calyculin A inhibited approximately 100% of both PP-2A and PP-1, approximately 80% of GSK-3, approximately 50% of cdk5 and approximately 30% of cdc2 but neither inhibited PKA nor resulted in the hyperphosphorylation of tau at any of the above sites. These studies suggest (i) that PP-1 upregulates the phosphorylation of tau at Ser 198/199/202 and Ser 396/404 indirectly by regulating the activities of GSK-3, cdk5 and cdc2 whereas PP-2A regulates the phosphorylation of tau directly by dephosphorylation at the above sites, and (ii) that a decrease in the PP-2A activity leads to abnormal hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422.
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PMID:Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. 1108 71

Glycogen synthase kinase 3 (GSK-3), an element of the Wnt signalling pathway, plays a key role in numerous cellular processes including cell proliferation, embryonic development, and neuronal functions. It is directly involved in diseases such as cancer (by controlling apoptosis and the levels of beta-catenin and cyclin D1), Alzheimer's disease (tau hyperphosphorylation), and diabetes (as a downstream element of insulin action, GSK-3 regulates glycogen and lipid synthesis). We describe here a rapid and efficient method for the purification of GSK-3 by affinity chromatography on an immobilized fragment of axin. Axin is a docking protein which interacts with GSK-3ss, beta-catenin, phosphatase 2A, and APC. A polyhistidine-tagged axin peptide (residues 419-672) was produced in Escherichia coli and either immobilized on Ni-NTA agarose beads or purified and immobilized on CNBr-activated Sepharose 4B. These "Axin-His6" matrices were found to selectively bind recombinant rat GSK-3 beta and native GSK-3 from yeast, sea urchin embryos, and porcine brain. The affinity-purified enzymes displayed high kinase activity. This single step purification method provides a convenient tool to follow the status of GSK-3 (protein level, phosphorylation state, kinase activity) under various physiological settings. It also provides a simple and efficient way to purify large amounts of active recombinant or native GSK-3 for screening purposes.
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PMID:Purification of GSK-3 by affinity chromatography on immobilized axin. 1108 79

Neurofibrillary tangles, which contain abnormally hyperphosphorylated forms of tau protein, are one of the neuropathological hallmarks of Alzheimer's disease (AD). This altered phosphorylation state of tau protein may be due to increased kinase activity or/and decreased phosphatase activity. In the present study, we characterized human calcineurin phosphatase activity in postmortem superior frontal cortex and sensorimotor cortex and measured calcineurin phosphatase activity in samples from individuals with moderate to severe AD (n = 7) and age-matched controls (n = 5). Basal phosphatase activity was reduced by 25% (P < 0.05) in AD frontal cortex. Nickel-stimulated calcineurin activity was decreased by 52% (P < 0.05) and 30% (P < 0.05) in P2 and total cell homogenate, respectively, compared to age-matched controls. No differences in phosphatase activities were detected in the sensorimotor cortex. The decrease in nickel-stimulated calcineurin phosphatase activity in frontal lobe correlated with the neurofibrillary tangle pathology (total cell homogenate, r = -0.77, P < 0.05; P2 fraction, r = -0.76, P < 0.02), but not with diffuse or neuritic plaques. Despite the changes in calcineurin phosphatase activity in the superior frontal cortex, calcineurin protein levels determined by immunoblot were similar in control and AD cases. In addition, no changes in calcineurin regulatory proteins (cyclophilin A and FKBP12) levels were observed. These studies suggest that decrease of calcineurin activity may play a role in paired-helical filament formation and/or stabilization, and the decrease of activity was not accompanied by a decrease of calcineurin protein expression.
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PMID:Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer's disease cerebral cortex. 1116 3

Since abnormal tau phosphorylation may play a role in neurofibrillary tangle (NFT) formation in aging and Alzheimer's disease (AD), we probed the distribution and abundance of protein phosphatase 2A (PP2A) catalytic (Calpha) and regulatory (PR55alpha and gamma, PR61varepsilon and delta) subunit mRNA in control and AD hippocampus using in situ hybridization. Quantitation of grain density per neuron area of PP2A subunits and beta-actin was determined for the CA3 region of hippocampus and cerebellum, while a qualitative assessment was performed for CA1, CA4, and dentate gyrus. All subunits are expressed in neurons, while PR55gamma and PR55alpha mRNA are also evident in glia. The expression levels of Calpha, all PP2A regulatory subunits studied, and beta-actin were similar in control and AD cerebellum. beta-Actin mRNA was, however, reduced in AD hippocampus. In addition to the generalized reduction of mRNA, as indicated by decreased beta-actin signal, there was a significant loss of Calpha, PR55gamma, and PR61epsilon mRNA in the CA3 hippocampus of AD. This study delineates the distribution of critical PP2A mRNAs and reveals a neuron- and subunit-specific reduction in PP2A catalytic and regulatory mRNA in AD hippocampus. This could result in decreased protein expression and phosphatase activity, leading to the hyperphosphorylation of tau and the formation of NFTs, as well as neuron degeneration in AD.
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PMID:PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus. 1125 28


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