Characterization of excitotoxicity induced transcriptional dysregulation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184681 | GEO | 2025/10/03
REPOSITORIES: GEO
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Project description:Glutamate excitotoxicity plays a critical role in neurodegeneration by triggering NMDA receptorhyperactivation, leading to elevated synaptic calcium levels and subsequent neuronal cell death. Tobetter understand how glutamateaffects neurons in neurological diseases, we conducted acomprehensive analysis of molecular changes at the transcriptome and kinome levels.Our research used primary cortical cultures from rat embryos to study glutamate excitotoxicity. Non-neuronal cells,like astrocytes, typically enhance neuron tolerance to glutamate excitotoxicity. We useda neuron-rich cultured system and observed that the effects of glutamate on neurons are concentration-dependent. Intermediate doses of glutamate had significant neurotoxic effects, while high and lowdoses resulted in less cell mortality, aligning with previous findings related to calcium influx.Glutamate is known to inhibit protein synthesis in neurons and leads to a rise in cytosolic calcium, a keystep in synapticplasticity and delayed neuronal cell death. Kinome profiling indicated activation of PKAand PKG phosphorylation, essential for synaptic plasticity-related gene expression.
2024-05-28 | GSE255041 | GEO
Project description:Excitotoxicity is a major pathologic mechanism in patients with tauopathy and other neurodegenerative diseases. However, the key neurotoxic drivers and most effective strategies for mitigating these degenerative processes are unclear. Here, we show that glutamate treatment of induced pluripotent stem cell (iPSC)-derived cerebral organoids induces tau oligomerization and neurodegeneration, and that these phenotypes are enhanced in organoids derived from tauopathy patients. Using a genome-wide CRISPR interference (CRISPRi) screen, we find that suppression of KCTD20 potently ameliorates tau pathology and neurodegeneration in glutamate-treated organoids and mice, as well as in transgenic mice overexpressing mutant human tau. KCTD20 suppression reduces oligomeric tau and improves neuron survival by activating lysosomal exocytosis, which clears pathological tau. Our results show that glutamate signaling can induce neuronal tau pathology and identify KCTD20 suppression and lysosomal exocytosis as effective strategies for clearing neurotoxic tau species.
2025-02-28 | GSE287664 | GEO
Project description:Excitotoxicity is a primary pathological process directing neuronal cell death in both acute neurological disorders and neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease. We use mouse cultured cortical neuron treated with 100uM of Glutamate for a model of excitotoxicity and applied N-terminomics (TAILS) method to identify the neuronal proteins aberrantly modified in excitotoxicity
2023-04-07 | PXD040648 | Pride
Project description:Excitotoxicity caused by over-stimulation of the ionotropic glutamate receptors is a key neuronal cell death process underpinning brain damage in acute and chronic neurological disorders such as ischaemic stroke, traumatic brain injury, and neurodegenerative diseases. Exactly how neurons die in excitotoxicity still remains unclear and is an important area of research in the field of neuroscience. In this current project we wanted to explore the global changes in proteome and phosphoproteome following glutamate excitotoxicity in cultured primary cortical neurons.
2019-03-07 | PXD008353 | Pride
Project description:In recent decades, transcriptome analysis has been widely used to understand human disease pathogenesis and identify therapeutic targets and biomarkers. Accumulated reports in patients with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, have also provided evidence of dysregulated gene expression related to neuropathogenesis. However, obtaining samples from neurodegenerative patients is more challenging than other human diseases due to low accessibility. Also, brain tissues and cerebrospinal fluid are composed of multiple cell types, so they are unsuitable for obtaining neural cell-type-specific gene expression profiles. Thus, we here report gene expression profiles in primary neuronal cultures exposed to Aβ toxicity and glutamate excitotoxicity to understand pathological gene expression in neurons. By RNA-sequencing analysis, we compare transcriptomes and find that two groups of genes show similar expression patterns in Aβ toxicity excitotoxicity—they are either up- or down-regulated in both conditions. Genes in the two groups are related to synaptic function and cell signaling, which are well-known biological functions altered in Aβ toxicity and excitotoxicity. Interestingly, the analysis reveals a possibility that circadian clock (molecular oscillator generating daily rhythms)-related genes are dysregulated in both conditions. We confirm the reduced circadian transcription factor Bmal1 levels in Aβ toxicity and glutamate excitotoxicity. RNA-sequencing analysis in Bmal1-deleted neurons shows potential relationships between BMAL1 and synaptic functions. Thus, this transcriptome study provides evidence of the potential roles of the circadian clock in neuropathogenesis.
2025-06-14 | GSE206081 | GEO
Project description:REST has been initially described as a repressor of neuronal genes in non-neuronal cells by binding to its recognition sequence RE1. Over-activation of this factor has been shown in several diseases such as Huntington disease or central nervous system cancers. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to the identification of one benzoimidazole-5-carboxamide derivative (X5050) that inhibited REST silencing in a RE1-dependent manner. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST.
2013-10-01 | GSE40695 | GEO
Project description:Background Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in a triad of behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. OVT73 captures an early prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. Methods To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. Results We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in OVT73 medium spiny neurons, the cell type preferentially lost early in HD. This observation supports the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process. Moreover, we also observed the downstream consequences of excitotoxic stress, including a downregulation of transcription of components for the oxidative phosphorylation complexes. We also found that pathways whose activity has been proposed to reduce excitotoxicity, including the CREB family of transcription factors (CREB1, ATF2, ATF4 and ATF7) were transcriptionally downregulated. Conclusions To our knowledge, the OVT73 model is the first large mammal HD model that exhibits transcriptomic signatures of an excitotoxic process in the absence of neuronal loss. Our results suggest that glutamate excitotoxicity is a disease-initiating process. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.
2023-07-06 | GSE229839 | GEO
Project description:REST has been initially described as a repressor of neuronal genes in non-neuronal cells by binding to its recognition sequence RE1. Over-activation of this factor has been shown in several diseases such as Huntington disease or central nervous system cancers. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to the identification of one benzoimidazole-5-carboxamide derivative (X5050) that inhibited REST silencing in a RE1-dependent manner. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST. RNA was extracted from 6 samples, corresponding to 3 independent cultures of NSC SA-01, each one treated either with DMSO (0.1 % final) or with X5050 (100 õM final). RNA was isolated using RNeasy Mini kit with DNase I digestion and genome-wide gene expression profiling was performed by hybridization on Affymetrix microarrays
2013-10-01 | E-GEOD-40695 | biostudies-arrayexpress
Project description:In this study, we investigated the mechanisms of neuroprotection of factors secreted by glial progenitro cells. We earlier obtainedn data on their neuroprotective action on the model of glutamate excitotoxicity, as well as proteomic analysis. The model was reproduced on cortical neuron cultures from rat pups (P0, 10 DIV). Before the model reproducing, the samples were added. Next day a solution containing 100 μM glutamate was added to the cultures for 1 hour. The negative control was intact cultures. The addition of 100 μM memantine was a positive control. Three repeats were performed for each group and both controls. The comparison groups were: extracellular vesicles, proteins of the 3-100 kDa fraction and total secretome. Total RNA was collected 4 hours after model reproducing for transcriptome analysis to identify signaling pathways activated in cells by druges under induced glutamate toxicity.
2025-09-15 | GSE282138 | GEO
Project description:Neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. Candesartan significantly reduced glutamate-induced inflammation. To provide mechanistic insight into the potential targets and pathways that may underlie these benefits, we performed genome wide expression profile analysis and evaluated the data by Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). We found that the inflammation signal transduction pathways were major components of the neuronal response to glutamate excitotoxicity, and that candesartan significantly ameliorated glutamate-induced alterations in gene expression. Further analysis showed significant associations of these genes with two independent published networks identified by microarray analysis of hippocampal samples obtained post-mortem from brains of patients diagnosed with AD . 8 days old rat Primary cerebellar granule cells (CGCs) were treated with DMSO, Glutamate, Candesartan or Glutamate +candesartan. Four replicates of each treatment were done.
2016-03-17 | E-GEOD-67036 | biostudies-arrayexpress