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)

The paired helical filament (PHF), which comprises the major fibrous element of the neurofibrillary tangle of Alzheimer's disease, is composed of abnormally phosphorylated microtubule-associated protein tau. Here we show that p42 MAP kinase phosphorylates recombinant tau and converts it to a form which is similar to PHF tau. Of the major serine/threonine protein phosphatases found in mammalian tissues only protein phosphatase 2A (PP2A) could dephosphorylate tau phosphorylated in this manner, with PP2A1 being the most effective form of the enzyme.
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PMID:p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. 133 Jun 87

Extracellular deposition of the beta/A4 amyloid peptide is a characteristic feature of the brain in patients with Alzheimer disease. beta/A4 amyloid is derived from the amyloid precursor protein (APP), an integral membrane protein that exists as three major isoforms (APP695, APP751, and APP770). Secreted forms of APP found in blood plasma and cerebrospinal fluid arise by proteolytic cleavage of APP within the beta/A4 amyloid domain, precluding the possibility of amyloidogenesis for that population of molecules. In the present study, we have demonstrated that treatment of PC12 cells with phorbol ester produces a severalfold increase in secretion of APP695, APP751, and APP770. This increase is augmented by simultaneous treatment with the protein phosphatase inhibitor okadaic acid. These data indicate that protein phosphorylation regulates intra-beta/A4 amyloid cleavage and APP secretion. These and other results suggest that APP molecules can normally follow either of two processing pathways: regulated secretion or proteolytic degradation unassociated with secretion.
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PMID:Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. 155 13

The incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) among the Chamorros in Guam is remarkably high. The patients with ALS have clinical and pathological characteristics similar to those in other parts of the world. The PDC patients display parkinsonism and progressive dementia and show a characteristic neuronal loss in certain parts of the central nervous system such as the hippocampus and substantia nigra. The Guamanian patients with ALS and PDC commonly have widespread Alzheimer's neurofibrillary changes, but without the associated senile plaques. We have applied immunohistochemical procedures to examine the expression of marker substances in Guamanian ALS and PDC. The markers studied include tau protein, ubiquitin, beta proteins, synaptophysin, calcineurin, Met-enkephalin, substance P and tyrosine hydroxylase. The results were compared with the findings in patients with Alzheimer's disease, Parkinson's disease, sporadic ALS and familial ALS.
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PMID:Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam: immunohistochemical studies. 158 17

A comparative topographical immunohistochemical analysis was performed on the basal ganglia (including the substantia nigra) in Guamanian parkinsonism-dementia complex, idiopathic Parkinson's disease (PD), and Alzheimer's disease (AD). The striatal projection neurons and their efferent fibers were examined by using antibodies to calcineurin, methionine-enkephalin, and substance P. Tyrosine hydroxylase served as a marker for nigrostriatal dopaminergic neurons. The basal ganglia of patients with parkinsonism-dementia complex reacted strongly with all of the antibodies and the reaction products exhibited a normal distribution pattern. These findings suggest that the striatal output system is well preserved in patients with this disease. Similar results were obtained in patients with AD or PD. However, as compared to the patients with AD or PD, patients with parkinsonism-dementia complex showed severe reduction (greater than 90%) in the number of dopaminergic neurons in both the lateral and the medial portions of the substantia nigra. In view of the functional cortico-subcortical loops, these findings could explain the parkinsonian features and in part the cognitive impairment that occur in parkinsonism-dementia complex on Guam.
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PMID:Immunohistochemical study of the striatal efferents and nigral dopaminergic neurons in parkinsonism-dementia complex on Guam in comparison with those in Parkinson's and Alzheimer's diseases. 169 18

To investigate the regulation of posttranslational modifications of tau that might be pertinent to the production of the paired helical filament (PHF) of Alzheimer's disease, we incubated human neuroblastoma cells with the protein phosphatase inhibitor okadaic acid. This treatment results in increased immunoreactivity of tau with the monoclonal antibodies Alz-50, PHF-1, T3P, and NP8, a reduction in Tau-1 immunoreactivity, and an elevation in apparent molecular weight of tau. Moreover, our data demonstrate that accumulation of phosphates in tau leads to a decrease in the turnover rate of tau in the neuroblastoma cells. It is suggested that similar build-up of hyperphosphorylated tau in the neuronal perikarya may represent an early event in PHF formation. The present system facilitates the investigation of regulatory mechanisms governing the occurrence of PHF epitopes, their effects on neuronal cell metabolism, and possible pharmacological intervention.
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PMID:Increased production of paired helical filament epitopes in a cell culture system reduces the turnover of tau. 750 14

Tau protein-prepared post-mortem from brains of Alzheimer's disease patients was treated with protein phosphatase 1 catalytic subunit, 2A catalytic subunit, and 2B (calcineurin). Dephosphorylation was monitored by immunoblotting with two monoclonal antibodies, TAU-1 and SMI31, which recognize in tau the dephospho- and phospho-states, respectively, of proline-directed protein kinase phosphorylation sites. Out of the three enzymes tested, protein phosphatase 2A was only effective in dephosphorylating tau at these Alzheimer-type epitopes.
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PMID:Dephosphorylation of tau protein from Alzheimer's disease patients. 751 23

We have previously shown that a brain protein kinase, termed PK40, catalyzes the multiple phosphorylation of the KSP-repeat site of neurofilaments (NFs) and also can transform tau proteins into the paired helical filament-like state as found in Alzheimer's disease (AD) brains. Protein sequence analysis suggests that PK40 is a form of the extracellular signal-regulated kinase ERK2. A subpopulation of ERK2 species in soluble brain fractions can be efficiently phosphorylated and activated in cell-free systems, simply by adding Mg(2+)-ATP. Two phosphoisoforms of PK40erk2 are formed in this process, which have a reduced gel mobility, very much like the ERK2 form obtained in cell culture by stimulation with growth factors. One of these low-mobility forms cannot be inactivated with protein phosphatase 2A (PP2A) or with tyrosine phosphatases. The second form can be slowly inactivated by PP2A. In this case two Ser/Thr phosphates are removed at different rates during inactivation: One phosphate is very quickly removed to result in the formation of a high-mobility 39-kDa ERK2 species without consequence for activity; the other, slowly removed Ser/Thr phosphate controls the activity but has no effect on the gel mobility of ERK2. These results show that forms of ERK2 exist with properties different from the previously characterized ERK2 (p42mapk) from stimulated cell cultures. The active ERK2 forms produced in the presence of Mg(2+)-ATP alone could provide an explanation for the existence of constitutive ERK2-like NF phosphorylation in vivo. Excessive formation of an ERK2 species resistant to inactivation by PP2A might be relevant to the persistent pathological tau hyperphosphorylation in AD.
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PMID:Phosphatase resistance of ERK2 brain kinase PK40erk2. 753 8

We consider the interactions of tau protein with microtubules from two points of view, phosphorylation and domain structure. Tau can be phosphorylated at many sites and by several kinases, notably by proline-directed kinases (MAPK, GSK-3, cdk5) which generate Alzheimer-like antibody epitopes. Other kinases phosphorylate Ser 262, a site that has a particularly pronounced influence on the affinity of tau for microtubules. All of these sites can be cleared by phosphatases PP-2a and calcineurin. The site Ser262 lies within the repeat domain of tau. However, when probing the domains of tau for their effects on microtubule binding, nucleation, assembly, or bundling, the repeat domain has only a weak influence. Whereas the repeat domain of tau binds to microtubules with low affinity, repeat-less tau binds strongly yet unproductively in terms of microtubule assembly. Productive binding of tau to microtubules depends on the combination of (some) repeats with the flanking regions, as if the flanking regions acted as "jaws" for the proper positioning of tau on the microtubule surface.
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PMID:Tau domains, phosphorylation, and interactions with microtubules. 756 45

The paired helical filament (PHF), which makes up the major fibrous component of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated and abnormally phosphorylated microtubule-associated protein tau. Previous studies have identified serine and threonine residues phosphorylated in PHF-tau and have shown that tau can be phosphorylated at several of these sites by proline-directed protein kinases and cyclic AMP-dependent protein kinase. Here we have investigated which protein phosphatase activities can dephosphorylate recombinant tau phosphorylated with mitogen-activated protein kinase, glycogen synthase kinase-3 beta, neuronal cdc2-like kinase, or cyclic AMP-dependent protein kinase. We show that protein phosphatase 2A is by far the major protein phosphatase activity in brain that dephosphorylates tau phosphorylated in this manner.
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PMID:Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. 759 82

The accumulation of hyperphosphorylated tau species in neurons in Alzheimer's disease (AD) might result from a relative decrease in their content of protein phosphatases. In this study we have investigated the immunocytochemical distribution of calcineurin (phosphatase 2B) in the hippocampus and temporal cortex of human control subjects and in AD. Calcineurin was strongly expressed in neuronal perikarya and dendrites but only weakly in white matter tracts, both in controls and in AD. The distribution of calcineurin was preserved in AD. By double-immunolabelling with calcineurin antibodies and the AT8 antibody to paired helical filament-tau, it was observed that a strong calcineurin immunoreactivity was still present in many neurons containing neurofibrillary tangles (NFT). Calcineurin was present in dystrophic neurites in some senile plaques (SP) located in the hippocampal formation but more rarely in neocortical areas; this calcineurin immunoreactivity did not always overlap with the tau immunoreactivity in SP. These results suggest that development of NFT in most neurons does not result from a major decrease of calcineurin expression.
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PMID:Calcineurin (phosphatase 2B) is present in neurons containing neurofibrillary tangles and in a subset of senile plaques in Alzheimer's disease. 760 Jan 82


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