Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage

Zhai, Dongxu; Chin, Kyle; Wang, Min; Liu, Fang

doi:10.1186/1756-6606-7-20

Cited by 56 publications

(38 citation statements)

References 67 publications

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“…Previous studies have shown that AMPA receptor antagonists can ameliorate autoimmune encephalomyelitis, by promoting neuron, oligodendrocyte, and axon survival, and rescuing demyelination in the spinal cords of EAE rats and mice . We have shown previously that disruption of the GluR2–GAPDH interaction can block AMPA receptor‐mediated neurotoxicity . To determine whether disruption of GluR2–GAPDH interaction has protective effects in EAE mice, we examined lumbar spinal cord sections from EAE mice treated with TAT‐G‐Gpep peptide in comparison to control peptide.…”

Section: Resultsmentioning

confidence: 99%

Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis

Zhai

Lee

D'Souza

et al. 2015

Ann Clin Transl Neurol

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ObjectiveMultiple sclerosis (MS) is the most common disabling neurological disease of young adults. The pathophysiological mechanism of MS remains largely unknown and no cure is available. Current clinical treatments for MS modulate the immune system, with the rationale that autoimmunity is at the core of MS pathophysiology.MethodsExperimental autoimmune encephalitis (EAE) was induced in mice with MOG35-55 and clinical scoring was performed to monitor signs of paralysis. EAE mice were injected intraperitoneally with TAT-fusion peptides daily from day 10 until day 30 after immunization, and their effects were measured at day 17 or day 30.ResultsWe report a novel target for the development of MS therapy, which aimed at blocking glutamate-mediated neurotoxicity through targeting the interaction between the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor and an interacting protein. We found that protein complex composed of the GluR2 subunit of AMPA receptors and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was present at significantly higher levels in postmortem tissue from MS patients and in EAE mice, an animal model for MS. Next, we developed a peptide that specifically disrupts the GluR2 -GAPDH complex. This peptide greatly improves neurological function in EAE mice, reduces neuron death, rescues demyelination, increases oligodendrocyte survival, and reduces axonal damage in the spinal cords of EAE mice. More importantly, our peptide has no direct suppressive effect on naive T-cell responses or basal neurotransmission.InterpretationThe GluR2 -GAPDH complex represents a novel therapeutic target for the development of medications for MS that work through a different mechanism than existing treatments.

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Section: Resultsmentioning

confidence: 99%

Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis

Zhai

Lee

D'Souza

et al. 2015

Ann Clin Transl Neurol

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“…Similarly, GAPDH complexes with p53 transcription factor to then transcriptionally activates different genes among which the p53 itself [ 170 ] ( Figure 4 ).…”

Section: Glyceraldehyde-3-phosphate Dehydrogenase (Gapdh) Binding mentioning

confidence: 99%

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

Savreux-Lenglet

Depauw

David-Cordonnier

2015

IJMS

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DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.

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“…In our previous studies, we have identified a novel interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and that an enhanced complex formation is associated with neuronal cell death 18 19 20 . GAPDH was shown to interact with p53 which subsequently promoted this cell death pathway via p53 phosphorylation 21 . This provided new insights about the cell signaling properties of the GluA2-GAPDH interaction.…”

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Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

Lee

Xie

et al. 2016

Sci Rep

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GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density. Consistently, in vivo data with mouse brains from pregnant dams injected with GluA2-G-Gpep daily during embryonic day 8 to 19 revealed a reduction of cortical tract axon integrity and neuronal density in post-natal day 1 offspring. Disruption of GluA2-GAPDH interaction also impairs the GluA2-Plexin A4 interaction and reduces p53 acetylation in mice, both of which are possible mechanisms leading to the observed neurodevelopmental abnormalities. Furthermore, electrophysiological experiments indicate altered long-term potentiation (LTP) in hippocampal slices of offspring mice. Our results provide novel evidence that AMPARs, specifically the GluA2 subunit via its interaction with GAPDH, play a critical role in cortical neurodevelopment.

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Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage

Cited by 56 publications

References 67 publications

Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis

Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

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