Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model

Corcoran, Niall M.; Martı́n, Daniel; Hutter‐Paier, Birgit; Windisch, Manfred; Nguyen, Thanh T.; Nheu, Lina; Sundström, Lars; Costello, Anthony J.; Hovens, Christopher M.

doi:10.1016/j.jocn.2010.04.020

Cited by 142 publications

(128 citation statements)

References 21 publications

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“…Pharmacological agents that increase microtubule-associated PP2A levels by interfering with ␣4 monoubiquitination or cleavage are an attractive avenue for the treatment of AD and other tauopathies. Two drugs that should be considered in this regard are metformin and sodium selenate as they have been shown to stabilize Tau-associated PP2A and reduce Tau phosphorylation in cellular and animal models of AD (35)(36)(37). In summary, our studies have uncovered a novel regulatory process for PP2A involving ubiquitination-induced cleavage of ␣4, which plays a crucial role in modulating PP2Ac levels in both normal and pathophysiological conditions.…”

Section: Discussionmentioning

confidence: 82%

Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit α4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

Watkins

Wang

Mazalouskas

et al. 2012

Journal of Biological Chemistry

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Background: ␣4 binds to the PP2A catalytic subunit and the microtubule-associated E3 ligase MID1. Results: MID1-dependent monoubiquitination promotes calpain-mediated cleavage of ␣4, altering its phosphatase regulatory function. Conclusion: Defects in this regulatory process may underlie the MAP hypophosphorylation and hyperphosphorylation seen in Opitz syndrome and Alzheimer disease. Significance: Pharmacological agents that interfere with ␣4 monoubiquitination or cleavage are potential therapeutics to treat Alzheimer disease.

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Section: Discussionmentioning

confidence: 82%

Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit α4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

Watkins

Wang

Mazalouskas

et al. 2012

Journal of Biological Chemistry

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“…Enhancing PP2A activity has also been shown to mitigate the pathology in an AD model as well: EHT treatment resulted in substantial amelioration of AD‐like pathologies such as tau hyperphosphorylation, elevated amyloid‐ β levels, and cognitive impairment in a rat model of AD generated by viral vector‐mediated expression of the PP2A endogenous inhibitor I2 PP2A , or SET protein, in the brain 19. And in aged mice and in transgenic tauopathy models of AD, the use of another enhancer of PP2A activity, sodium selenite, has also been demonstrated to reduce tau hyperphosphorylation 63, 64. Thus, PP2A modulation may provide a common approach for treating neurodegenerative proteinopathies associated with hyperphosphorylated pathogenic proteins.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.Results LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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“…Together with the observed behavioral deficits, our results suggest that the TMHT mice studied are a suitable model for 2N4R-generating tauopathies. In a first project, the TMHT mouse model was already used to analyze the effect of sodium selenate as an agonist for the PP2A phosphatase to promote dephosphorylation of tau, causing improved spatial learning and memory with concomitant reduction in tau phosphorylation [45]. The finding that biochemical, histological and behavioral parameters were all affected by the drug given in the study by Corcoran et al [45] suggests that TMHT mice are an appropriate model to study in vivo drug effects regulating tau hyperphosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…In a first project, the TMHT mouse model was already used to analyze the effect of sodium selenate as an agonist for the PP2A phosphatase to promote dephosphorylation of tau, causing improved spatial learning and memory with concomitant reduction in tau phosphorylation [45]. The finding that biochemical, histological and behavioral parameters were all affected by the drug given in the study by Corcoran et al [45] suggests that TMHT mice are an appropriate model to study in vivo drug effects regulating tau hyperphosphorylation. In combination with multisite mass spectrometry-based phosphorylation measurements, it will be further possible to confirm the mode of action of new drugs with unparalleled precision.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Flunkert¹,

Hierzer²,

Löffler³

et al. 2012

Neurodegener Dis

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Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr¹⁸¹, Ser¹⁹⁹, Thr²³¹ and Thr²³⁵), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser³⁹⁶ and Ser⁴⁰⁴ in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

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Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model

Cited by 142 publications

References 21 publications

Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit α4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

Monoubiquitination Promotes Calpain Cleavage of the Protein Phosphatase 2A (PP2A) Regulatory Subunit α4, Altering PP2A Stability and Microtubule-associated Protein Phosphorylation

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

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