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NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration.

Kwak YD, Ma T, Diao S, Zhang X, Chen Y, Hsu J, Lipton SA, Masliah E, Xu H, Liao FF - Mol Neurodegener (2010)

Bottom Line: We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI).Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control.This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, 874 Union Avenue, Memphis TN, 38163, USA. fliao@uthsc.edu.

ABSTRACT

Background: The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. Recently, PTEN has also been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. It has been reported that loss of PTEN protein, accompanied by Akt activation, occurs under excitotoxic conditions (stroke) as well as in Alzheimer's (AD) brains. However the molecular signals and mechanism underlying PTEN loss are unknown.

Results: In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H2O2-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.

Conclusion: This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O2-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.

No MeSH data available.


Related in: MedlinePlus

Down regulation of PTEN is neuroprotective in acute experimental models. (A) and (B) Downregulation of PTEN with specific siRNA confers neuroprotection 24 h after Aβ exposure (25 μM): PTEN IHC staining (red, A) and MAP/NeuN staining for neuron morphology (green, B). (C) Reduced PTEN protein level in PTEN heterozygous mouse brain (frontal region), accompanied by elevated P-Akt level (2-month-old mice, n = 2). (D) Primary cultured cortical neurons from PTEN +/- pups manifest less apoptotic cell death than PTEN+/+ neurons 24 h after Aβ exposure. Data presented as means ± SD from 5 independent experiments.
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Figure 7: Down regulation of PTEN is neuroprotective in acute experimental models. (A) and (B) Downregulation of PTEN with specific siRNA confers neuroprotection 24 h after Aβ exposure (25 μM): PTEN IHC staining (red, A) and MAP/NeuN staining for neuron morphology (green, B). (C) Reduced PTEN protein level in PTEN heterozygous mouse brain (frontal region), accompanied by elevated P-Akt level (2-month-old mice, n = 2). (D) Primary cultured cortical neurons from PTEN +/- pups manifest less apoptotic cell death than PTEN+/+ neurons 24 h after Aβ exposure. Data presented as means ± SD from 5 independent experiments.

Mentions: In cultured primary neurons, exposure to Aβ or NMDA induced a rapid decrease in PTEN and increase in P-Akt levels. Downregulation of endogenous PTEN via specific siRNA produces neuroprotection, as evidenced by preserved neuronal structures (Figure 7A and 7B; MAP2/NeuN staining/Green). Moreover, the frontal region of the brain of PTEN heterozygous mice bear reduced PTEN as compared to WT littermate controls (~50% reduction) and increased basal P-Akt levels (Figure 7C). Cortical neurons from PTEN+/- brains exhibited increased resistance to Aβ-induced cell death compared to those from WT littermate controls (Figure 7D), suggesting a neuroprotective role for PTEN downregulation.


NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration.

Kwak YD, Ma T, Diao S, Zhang X, Chen Y, Hsu J, Lipton SA, Masliah E, Xu H, Liao FF - Mol Neurodegener (2010)

Down regulation of PTEN is neuroprotective in acute experimental models. (A) and (B) Downregulation of PTEN with specific siRNA confers neuroprotection 24 h after Aβ exposure (25 μM): PTEN IHC staining (red, A) and MAP/NeuN staining for neuron morphology (green, B). (C) Reduced PTEN protein level in PTEN heterozygous mouse brain (frontal region), accompanied by elevated P-Akt level (2-month-old mice, n = 2). (D) Primary cultured cortical neurons from PTEN +/- pups manifest less apoptotic cell death than PTEN+/+ neurons 24 h after Aβ exposure. Data presented as means ± SD from 5 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992530&req=5

Figure 7: Down regulation of PTEN is neuroprotective in acute experimental models. (A) and (B) Downregulation of PTEN with specific siRNA confers neuroprotection 24 h after Aβ exposure (25 μM): PTEN IHC staining (red, A) and MAP/NeuN staining for neuron morphology (green, B). (C) Reduced PTEN protein level in PTEN heterozygous mouse brain (frontal region), accompanied by elevated P-Akt level (2-month-old mice, n = 2). (D) Primary cultured cortical neurons from PTEN +/- pups manifest less apoptotic cell death than PTEN+/+ neurons 24 h after Aβ exposure. Data presented as means ± SD from 5 independent experiments.
Mentions: In cultured primary neurons, exposure to Aβ or NMDA induced a rapid decrease in PTEN and increase in P-Akt levels. Downregulation of endogenous PTEN via specific siRNA produces neuroprotection, as evidenced by preserved neuronal structures (Figure 7A and 7B; MAP2/NeuN staining/Green). Moreover, the frontal region of the brain of PTEN heterozygous mice bear reduced PTEN as compared to WT littermate controls (~50% reduction) and increased basal P-Akt levels (Figure 7C). Cortical neurons from PTEN+/- brains exhibited increased resistance to Aβ-induced cell death compared to those from WT littermate controls (Figure 7D), suggesting a neuroprotective role for PTEN downregulation.

Bottom Line: We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI).Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control.This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, University of Tennessee Health Science Center, College of Medicine, 874 Union Avenue, Memphis TN, 38163, USA. fliao@uthsc.edu.

ABSTRACT

Background: The phosphatase PTEN governs the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway which is arguably the most important pro-survival pathway in neurons. Recently, PTEN has also been implicated in multiple important CNS functions such as neuronal differentiation, plasticity, injury and drug addiction. It has been reported that loss of PTEN protein, accompanied by Akt activation, occurs under excitotoxic conditions (stroke) as well as in Alzheimer's (AD) brains. However the molecular signals and mechanism underlying PTEN loss are unknown.

Results: In this study, we investigated redox regulation of PTEN, namely S-nitrosylation, a covalent modification of cysteine residues by nitric oxide (NO), and H2O2-mediated oxidation. We found that S-nitrosylation of PTEN was markedly elevated in brains in the early stages of AD (MCI). Surprisingly, there was no increase in the H2O2-mediated oxidation of PTEN, a modification common in cancer cell types, in the MCI/AD brains as compared to normal aged control. Using several cultured neuronal models, we further demonstrate that S-nitrosylation, in conjunction with NO-mediated enhanced ubiquitination, regulates both the lipid phosphatase activity and protein stability of PTEN. S-nitrosylation and oxidation occur on overlapping and distinct Cys residues of PTEN. The NO signal induces PTEN protein degradation via the ubiquitin-proteasome system (UPS) through NEDD4-1-mediated ubiquitination.

Conclusion: This study demonstrates for the first time that NO-mediated redox regulation is the mechanism of PTEN protein degradation, which is distinguished from the H2O2-mediated PTEN oxidation, known to only inactivate the enzyme. This novel regulatory mechanism likely accounts for the PTEN loss observed in neurodegeneration such as in AD, in which NO plays a critical pathophysiological role.

No MeSH data available.


Related in: MedlinePlus