Phosphatase PTEN in neuronal injury and brain disorders

Chang, Ning; El-Hayek, Youssef; Gomez, Everlyne; Wan, Qi

doi:10.1016/j.tins.2007.08.006

Cited by 70 publications

(56 citation statements)

References 64 publications

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“…2 Recent studies have shown that suppressing PTEN protects against ischemic neuron death through both the enhancement of Akt activation and the inhibition of NR2B subunit-containing N-methyl-Daspartate receptors. 3,4 These data suggest that PTEN may be a therapeutic target for stroke treatment. However, the cellular and molecular mechanisms underlying PTEN downregulation-mediated neuroprotection remain largely unknown.…”

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confidence: 93%

“…However, the cellular and molecular mechanisms underlying PTEN downregulation-mediated neuroprotection remain largely unknown. 3 Ischemia-induced loss of excitatory and inhibitory equilibrium contributes to excitotoxicity-mediated neuronal death in ischemic stroke. Suppressed function of ␥-aminobutyric acid subtype A receptors (GABA A Rs) causes neuronal damage after stroke.…”

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confidence: 99%

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Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Liu

Zhang

et al. 2010

Stroke

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Background and Purpose-Downregulation of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is thought to be a novel neuroprotective strategy in ischemic stroke, but the underlying mechanisms remain unclear. In this study, we aimed to validate the use of PTEN regulation of ␥-aminobutyric acid subtype A receptors (GABA A Rs) as a molecular target for the treatment of ischemic stroke. Because suppression of GABA A Rs contributes to ischemic neuron death, describing the intracellular signaling that interacts with GABA A Rs in ischemic neurons would provide a molecular basis for novel stroke therapies. Methods-We measured surface GABA A R expression by immunocytochemical labeling and surface protein biotinylation assay. Knockdown and overexpression approaches were used to test the effects of PTEN on the expression and function of GABA A Rs. Neuronal death was detected in both in vitro and in vivo stroke models. Results-The knockdown and overexpression approaches provided the first evidence that PTEN negatively regulated membrane expression and function of GABA A Rs in rat hippocampal neurons. Importantly, we demonstrated that a PTEN inhibitor prevented the reduction of surface GABA A Rs in injured hippocampal neurons subjected to oxygen-glucose deprivation, an in vitro insult that mimics ischemic injury, whereas a GABA A R antagonist significantly reduced this PTEN inhibitor-induced neuroprotection in both the in vitro and in vivo ischemic stroke models. Conclusions-Our study provides direct evidence that downregulation of PTEN protects against ischemic neuron death by preserving GABA A R function. Targeting this pathway may be an effective strategy for development of selective, potent stroke treatments.

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confidence: 93%

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confidence: 99%

Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Liu

Zhang

et al. 2010

Stroke

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“…Studies by others and us have revealed that suppression of PTEN (phosphatase and tensin homolog) protects against neuronal death (Chang et al, 2007;Ning et al, 2004). Although it functions in the cytoplasm, PTEN can enter the nucleus to regulate transcription, alternative splicing and mRNA stability (Planchon et al, 2008).…”

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confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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SummaryThe dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

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“…The mice exhibited a similar phenotype to the first described model [114], and showed PTEN has been demonstrated to play a critical role in the regulation of neuronal development, axonal growth and regeneration, synaptic plasticity, neuronal survival and differentiation [117]. The functions of PTEN are mediated by the PI3K/mTOR [58] and MAPK [31,32] pathways.…”

Section: Rosmentioning

confidence: 52%

PTEN: A molecular target for neurodegenerative disorders

Ismail

Ning

Al-Hayani

et al. 2012

Translational Neuroscience

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PTEN: a molecular target for neurodegeneratIve dIsorders abstract PTEN (phosphatase and tensin homologue deleted in chromosome 10) was first identified as a candidate tumour suppressor gene located on chromosome 10q23. It is considered as one of the most frequently mutated genes in human malignancies. Emerging evidence shows that the biological function of PTEN extends beyond its tumour suppressor activity. In the central nervous system PTEN is a crucial regulator of neuronal development, neuronal survival, axonal regeneration and synaptic plasticity. Furthermore, PTEN has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Recently increased attention has been focused on PTEN as a potential target for the treatment of brain injury and neurodegeneration. In this review we discuss the essential functions of PTEN in the central nervous system and its involvement in neurodegeneration.

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Phosphatase PTEN in neuronal injury and brain disorders

Cited by 70 publications

References 64 publications

Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

PTEN: A molecular target for neurodegenerative disorders

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Phosphatase PTEN in neuronal injury and brain disorders

Cited by 70 publications

References 64 publications

Preservation of GABA A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Preservation of GABA A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

PTEN: A molecular target for neurodegenerative disorders

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Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

Preservation of GABA _A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke