Vascular endothelial growth factor protects spinal cord motoneurons against glutamate‐induced excitotoxicity via phosphatidylinositol 3‐kinase

Tolosa, Laia; Mir, Margalida; Asensio, Víctor J.; Olmos, Gabriel; Lladó, Jerònia

doi:10.1111/j.1471-4159.2007.05206.x

Cited by 97 publications

(68 citation statements)

References 52 publications

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“…However, there is no direct evidence showing the neuroprotective effect of endogenous TDP-43 in neuronal injury and neurodegeneration. Our study provides the first evidence that nuclear TDP-43 expression is increased at the early stages in an in vitro glutamate accumulation-induced neurodegeneration model (Corse et al, 1999;Kidd and Isaac 2000;Matyja et al, 2006;Nagańska et al, 2010;Tolosa et al, 2008;Van Westerlaak et al, 2001). We demonstrate that glutamate accumulation results in an (right) show that overexpression of TDP-43 or treatment with bpV(pic) reduces NR2AR inhibition-mediated increase of neuronal death at 3 days after 100 mM THA treatment (means 6 s.e.m.…”

Section: Discussionmentioning

confidence: 63%

“…DL-threo-betahydroxyaspartate (THA), an inhibitor of glutamate transporters, was used to induce neuronal injury. By promoting extracellular glutamate accumulation, THA treatment causes glutamate neurotoxicity and has been used to induce neuronal injury in vitro (Corse et al, 1999;Kidd and Isaac, 2000;Matyja et al, 2006;Nagańska et al, 2010;Tolosa et al, 2008;Van Westerlaak et al, 2001). To characterize this model, we first performed a lactate dehydrogenase (LDH) release assay to measure THAinduced neuronal damage in the cortical cultures.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

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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“…Although it is unrealistic to expect the transplantation of stem cells or stem cellderived motoneurons in ALS patients to replace lost neurons, to integrate into existing neural circuitry and restore motor function, provision of neurotrophic factors by transplanted stem cells to prevent cell death in host motoneurons is a realistic and achievable approach. 7 Recent studies have shown that the administration of vascular endothelial growth factor (VEGF) protected motoneurons against excitotoxin-mediated cell death in organotypic cultures and AMPA-infused rats, 14,15 and significantly delayed disease onset and prolonged the survival of ALS animal models. [16][17][18][19] VEGF is one of such growth factors that can be used in combination with transplanted stem cells to improve therapeutic efficiency of cellular transplantation.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice

et al. 2009

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“…In nonsmall cell lung cancer cell lines, activation of Dnmt1 can cause suppression of survivin gene expression and induce apoptosis [97]. Loss of survivin expression is associated with motor neuron degeneration in neonatal spinal cord organotypic slice cultures [98].…”

Section: Endogenous Dnmts Mediate Apoptosis In Cultured Motor Neuron-mentioning

confidence: 99%

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

Martin

Wong

2013

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS.

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Vascular endothelial growth factor protects spinal cord motoneurons against glutamate‐induced excitotoxicity via phosphatidylinositol 3‐kinase

Cited by 97 publications

References 52 publications

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

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

Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

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