In situ dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons

Saito, Taro; Ishiguro, Koichi; Uchida, Tsuneko; Miyamoto, Eishichi; Kishimoto, Takeo; Hisanaga, Shin‐ichi

doi:10.1016/0014-5793(95)01292-0

Cited by 51 publications

(23 citation statements)

References 36 publications

(33 reference statements)

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“…By using the abnormally hyperphosphorylated tau isolated from AD brain as a substrate, we have previously found that PP2A, PP2B, and, to a less extent, PP1 but not PP2C can efficiently dephosphorylate tau in vitro (12,(22)(23)(24). Similar findings have also been reported by using 32 P-labeled tau with various protein kinases as a substrate in vitro (25)(26)(27) or using in vivo phosphorylated tau as a substrate (27)(28)(29)(30). However, to date it is not known which of these three phosphatases regulates tau phosphorylation in vivo and by what mechanism tau is abnormally hyperphosphorylated in AD brain.…”

supporting

confidence: 72%

“…Slices-In vitro studies have suggested that PP2A and PP2B are the best candidate phosphatases involved in the regulation of the phosphorylation of tau (12,(22)(23)(24)(25)(26)(27)(28)(29)(30). Hence, we examined the phosphorylation of tau in these brain tissue slices when either PP2A or PP2B was selectively inhibited.…”

Section: Alzheimer-like Hyperphosphorylation and Accumulation Of Tau mentioning

confidence: 99%

“…In part, this is due to the lack of a model system for AD neurofibrillary lesions. Attempts to study the regulation of tau phosphorylation by protein phosphatases have been carried out in cultured cells (29,31), but this regulation in cultured cells is most likely different from that in mature mammalian brain. This is because all commonly used neuronal cell lines only express fetal type tau that is highly phosphorylated and composed of only the shortest isoform.…”

mentioning

confidence: 99%

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Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

Chen

Lidsky

Węgiel

et al. 2000

Journal of Biological Chemistry

393

265

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Hyperphosphorylated tau, which is the major protein of the neurofibrillary tangles in Alzheimer's disease brain, is most probably the result of an imbalance of tau kinase and phosphatase activities in the affected neurons. By using metabolically competent rat brain slices as a model, we found that selective inhibition of protein phosphatase 2A by okadaic acid induced an Alzheimerlike hyperphosphorylation and accumulation of tau. The hyperphosphorylated tau had a reduced ability to bind to microtubules and to promote microtubule assembly in vitro. Immunocytochemical staining revealed hyperphosphorylated tau accumulation in pyramidal neurons in cornu ammonis and in neocortical neurons. The topography of these changes recalls the distribution of neurofibrillary tangles in Alzheimer's disease brain. Selective inhibition of protein phosphatase 2B with cyclosporin A did not have any significant effect on tau phosphorylation, accumulation, or function. These studies suggest that protein phosphatase 2A participates in regulation of tau phosphorylation, processing, and function in vivo. A down-regulation of protein phosphatase 2A activity can lead to Alzheimer-like abnormal hyperphosphorylation of tau.

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supporting

confidence: 72%

Section: Alzheimer-like Hyperphosphorylation and Accumulation Of Tau mentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

Chen

Lidsky

Węgiel

et al. 2000

Journal of Biological Chemistry

393

265

View full text Add to dashboard Cite

show abstract

“…Hyperphosphorylated tau, an MAP, accumulates in intracellular neurofibrillary tangles and is associated with neurodegeneration and neuronal death in Alzheimer's disease. PP2A dephosphorylates MAPs, including tau (Ulloa et al, 1993;Saito et al, 1995;Gong et al, 2000), and reduced amounts of PP2A mRNA and protein are present in postmortem brains of Alzheimer's patients (Vogelsberg-Ragaglia et al, 2001;Sontag et al, 2004). Our data now demonstrate a physiological requirement for PP2A in organizing the synaptic cytoskeleton.…”

Section: Discussionmentioning

confidence: 56%

The B′ Protein Phosphatase 2A Regulatory Subunitwell-roundedRegulates Synaptic Growth and Cytoskeletal Stability at theDrosophilaNeuromuscular Junction

Viquez¹,

Li²,

Wairkar³

et al. 2006

J. Neurosci.

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Synaptic growth is essential for the development and plasticity of neural circuits. To identify molecular mechanisms regulating synaptic growth, we performed a gain-of-function screen for synapse morphology mutants at the Drosophila neuromuscular junction (NMJ). We isolated a BЈ regulatory subunit of protein phosphatase 2A (PP2A) that we have named well-rounded (wrd). Neuronal overexpression of wrd leads to overgrowth of the synaptic terminal. Endogenous Wrd protein is present in the larval nervous system and muscle and is enriched at central and neuromuscular synapses. wrd is required for normal synaptic development; in its absence, there are fewer synaptic boutons and there is a decrease in synaptic strength. wrd functions presynaptically to promote normal synaptic growth and postsynaptically to maintain normal levels of evoked transmitter release. In the absence of wrd, the presynaptic cytoskeleton is abnormal, with an increased proportion of unbundled microtubules. Reducing PP2A enzymatic activity also leads to an increase in unbundled microtubules, an effect enhanced by reducing wrd levels. Hence, wrd promotes the function of PP2A and is required for normal cytoskeletal organization, synaptic growth, and synaptic function at the Drosophila NMJ.

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“…Additionally, PPs are important regulators of tau phosphorylation. In neurons, okadaic acid causes hyperphosphorylation of tau, synapse modification, microtubule destabilization, and apoptosis (Harris et al, 1993;Saito et al, 1995;Fernandez-Sanchez et al, 1996;Garver et al, 1996;Malchiodi-Albedi et al, 1997;Merrick et al, 1997). PP1, PP2A, and PP2B (calcineurin) expression and/or activity have been found to be reduced greatly in AD brains compared with aged-matched control brains (Gong et al, 1993;Lian et al, 2001;Sontag et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

Yi¹,

Chung²,

Pang³

et al. 2005

J. Neurosci.

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The signaling pathways that mediate neurodegeneration are complex and involve a balance between phosphorylation and dephosphorylation of signaling and structural proteins. We have shown previously that 17␤-estradiol and its analogs are potent neuroprotectants. The purpose of this study was to delineate the role of protein phosphatases (PPs) in estrogen neuroprotection against oxidative stress and excitotoxicity. HT-22 cells, C6-glioma cells, and primary rat cortical neurons were exposed to the nonspecific serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A at various concentrations in the presence or absence of 17␤-estradiol and/or glutamate. Okadaic acid and calyculin A caused a dose-dependent decrease in cell viability in HT-22, C6-glioma, and primary rat cortical neurons. 17␤-Estradiol did not show protection against neurotoxic concentrations of either okadaic acid or calyculin A in these cells. In the absence of these serine/threonine protein phosphatase inhibitors, 17␤-estradiol attenuated glutamate toxicity. However, in the presence of effective concentrations of these protein phosphatase inhibitors, 17␤-estradiol protection against glutamate toxicity was lost. Furthermore, glutamate treatment in HT-22 cells and primary rat cortical neurons caused a 50% decrease in levels of PP1, PP2A, and PP2B protein, whereas coadministration of 17␤-estradiol with glutamate prevented the decrease in PP1, PP2A, and PP2B levels. These results suggest that 17␤-estradiol may protect cells against glutamate-induced oxidative stress and excitotoxicity by activating a combination of protein phosphatases.

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In situ dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons

Cited by 51 publications

References 36 publications

Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

The B′ Protein Phosphatase 2A Regulatory Subunitwell-roundedRegulates Synaptic Growth and Cytoskeletal Stability at theDrosophilaNeuromuscular Junction

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

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