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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2010

Open Access 01-12-2010 | Research article

NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration

Authors: Young-Don Kwak, Tao Ma, Shiyong Diao, Xue Zhang, Yaomin Chen, Janet Hsu, Stuart A Lipton, Eliezer Masliah, Huaxi Xu, Francesca-Fang Liao

Published in: Molecular Neurodegeneration | Issue 1/2010

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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.
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Metadata
Title
NO signaling and S-nitrosylation regulate PTEN inhibition in neurodegeneration
Authors
Young-Don Kwak
Tao Ma
Shiyong Diao
Xue Zhang
Yaomin Chen
Janet Hsu
Stuart A Lipton
Eliezer Masliah
Huaxi Xu
Francesca-Fang Liao
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2010
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-5-49

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