P53 prevents neurodegeneration by regulating synaptic genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE40418 | GEO | 2015/01/06
SECONDARY ACCESSION(S): PRJNA173918
REPOSITORIES: GEO
Similar Datasets
Project description:DNA damage has been implicated in neurodegenerative disorders, including Alzheimer’s disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration. 4 samples: tau vs. control
2015-01-06 | E-GEOD-40418 | biostudies-arrayexpress
Project description:Pathological aggregation of RNA binding proteins (RBPs) has emerged as an important driver of multiple neurodegenerative diseases. Since RBP aggregation may result in a loss of normal RBP function, we examined whether dysregulation of RNA metabolism contributes to tauopathies. We find that the PS19 P301S tau mouse model exhibits a dysregulation of RNA splicing that is also apparent upon analysis of human Alzheimer’s disease brain tissues. Dysregulated splicing particularly affected genes involved in synaptic transmission. We also analyzed alternative splicing in PS19 mice crossed to a heterozygous TIA1 background, which has recently been shown to slow disease progression. TIA1 reduction alleviated several of the most significant alternative splicing events for synaptic mRNA transcripts, suggesting that normalization of RBP functions is associated with the neuroprotection. We then used a systems biology approach termed NetDecoder to identify key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Importantly, pharmacological inhibition of MYC and EGFR activity in primary neurons overexpressing tau recapitulated the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, and identify new potential therapeutic targets for tauopathies.
2019-11-13 | GSE109226 | GEO
Project description:Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the exact roles of neuronal APOE4 in AD pathogenesis are still unclear. Here we report a rigorous characterization of neuronal APOE4 effects on prominent AD-related pathologies by selectively removing APOE4 from neurons in an APOE4-expressing tauopathy mouse model. We found that the removal of neuronal APOE4 led to a drastic reduction in Tau pathology accumulation and spread, gliosis, neurodegeneration, neurodysfunction, and myelin deficits in this tauopathy mouse model. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes, and microglia that were enriched in APOE4-expressing tauopathy mice and whose accumulation correlated to the severity of Tau pathology, neurodegeneration, and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can effectively combat APOE4-driven effects in AD and other tauopathies.
2023-01-06 | GSE221215 | GEO
Project description:Purpose: We investigated the molecular function of the nuclear protein, Akirin2 (Aki2), in postmitotic excitatory cortical neurons and neural progenitor cells of the embryonic dorsal telencephalon. Method: We performed total RNA-Sequencing on the cortex of P35 CaMK-Cre;Aki2fl/fl mice and age matched controls. We compared this transcriptomic database to one obtained through total RNA-Sequencing of E10.5 Emx1-Cre;Aki2fl/fl dorsal telencephalon and age-matched controls . Results: We discovered slow degeneration through necroptosis in the Aki2 postmitotic forebrain mutants and dysregulation of many p53 target genes in both transcriptomics datasets. Reduction of the p53 gene in the CaMK-Cre;Aki2fl/fl line delays cell death; while knockout prevents it entirely. Conclusion: This study provides insight into the molecular mechanisms of Aki2 function in cortical neurons and identifies p53 as a molecular mediator of neuronal death in the absence of Aki2. Futhermore, it identifies several candidate Aki2-dependent genes dysregulated in both transcroptomic datasets and many candidate Aki2 target genes that are context dependent.
2021-06-25 | GSE178844 | GEO
Project description:To investigate mutations in genes involved in the cellular import of dsRNA neuroprotection, we generated a profile of individual genes affected when dsRNA transport is incapacitated and established a foundation for the systemic analysis of their distinct contributions to neuroprotection. We then identified a set of previously unreported neuroprotective proteins using data obtained from RNA-seq.
2022-08-04 | GSE205118 | GEO
Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.
2011-05-01 | E-GEOD-26279 | biostudies-arrayexpress
Project description:Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T-cells blocked tau-mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN-γ and PD-1signaling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
2023-03-01 | GSE221856 | GEO
Project description:Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injuryin vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 μM) statistically significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 μM) and FLU (1 μM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 μM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGDdemonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, andthatTIA pretreatment counteracted theseeffects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.
2023-08-29 | GSE234798 | GEO
Project description:MicroRNAs (miRNAs) are short RNAs that regulate fundamental biological processes. miR-132, a key miRNA with established functions in Tau homeostasis and neuroprotection, is consistently downregulated in Alzheimer’s disease (AD) and other tauopathies. miR-132 overexpression rescues neurodegenerative phenotypes in several AD models. To complement research on miRNA-mimicking oligonucleotides targeting the central nervous system, we developed a high-throughput-screen coupled high-throughput-sequencing (HTS-HTS) in human induced pluripotent stem cell (iPSC)-derived neurons to identify small molecule inducers of miR-132. We discovered that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, selectively upregulated miR-132 in the sub-μM range. Coordinately, cardiac glycoside treatment downregulated total and phosphorylated Tau in rodent and human neurons and protected against toxicity by glutamate, N-methyl-D-aspartate, rotenone, and Aβ oligomers. In conclusion, we identified small-molecule drugs that upregulated the neuroprotective miR-132 and ameliorated neurodegenerative phenotypes. Our dataset also represents a comprehensive resource for discovering small molecules that modulate specific miRNAs for therapeutic purposes.
2023-10-19 | GSE216991 | GEO
Project description:In this dataset, we evalute the effect of modulating the levels of LSD1 in the PS19 tauopathy mouse (mouse that expresses the P301S mutated form of the human tau transgene). First we reduced the levels of LSD1 by crossing PS19 Tau mice with mice heterozygous for Lsd1. This results in an exacerbation of the neurodegenerative phenotype as well as an increase in the transcripational changes observed in taupoathy mice. Secondy, we overexprssed LSD1 in neurons of the adult tauopathy mouse through viral injection direclty into the hippocampus. This resulted in a reduce of neuronal cell death as well as the associated transcriptional changes.
2020-10-27 | GSE160151 | GEO