Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA323858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3609520.fastq.gz | Fastqsanger.gz | |||
| SRR3609530.fastq.gz | Fastqsanger.gz | |||
| SRR3609521.fastq.gz | Fastqsanger.gz | |||
| SRR3609531.fastq.gz | Fastqsanger.gz | |||
| SRR3609522.fastq.gz | Fastqsanger.gz |
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Project description:Rett syndrome is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here we report a test of the hypothesis of shared pathophysiology of Rett syndrome and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein synthesis-dependent synaptic plasticity is similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated ‘translatome’. We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that are functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5 negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In the Mecp2 KO mice we found that mGluR5 NAM treatment significantly reduces the level of overexpressed ribosome-associated transcripts, particularly those that are also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and life span. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through co-regulation of a subset of genes relevant to synaptic functions.
2016-12-31 | GSE82068 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24285: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (mm8 chromosomal tiling arrays) GSE24286: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (mm8 promoter tiling arrays) GSE24320: Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome (high-throughput small RNA sequencing) Refer to individual Series
2010-09-29 | E-GEOD-24329 | biostudies-arrayexpress
Project description:Longitudinal PET imaging of Alzheimer models reveals synaptic rescue by an mGluR5 modulator with selective normalization of neuronal transcriptomes. Alzheimer’s disease symptoms are initiated by synapse loss in the setting of microglial reactivity, but the basis for immune mediator attack on synapses is not clear. The mGluR5 silent allosteric modulator (SAM), BMS-984923, prevents Alzheimer’s triggered aberrant synaptic signaling while preserving physiological Glu activation. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB PET at doses 250-fold below adverse effect doses in rodent and non-human primate. For aged transgenic and double knock-in mouse Alzheimer’s models, SV2A PET imaging with [18F]SynVesT-1 reveals cortical and hippocampal synapse density decreases, which are fully recovered by SAM treatment. The disease-modifying benefit persists after drug washout. Tau accumulation in double knock-in mice is also reduced by SAM treatment. Single nuclei transcriptomics demonstrate that SAM treatment normalizes expression patterns to a much greater extent in neurons than glia. Production of the microglial mediator, C1q, is not altered by the mGluR5 compound, but Alzheimer gene-dependent C1q localization to synapses and synaptic engulfment are prevented. Thus, selective modulation of mGluR5 reverses neuronal gene expression changes to protect synapses from damage by microglial mediators.
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Project description:Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. Highest levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in L-1236 in comparison to classical Hodgkin lymphoma-controls. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g. EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin’s lymphoma in Ophelia syndrome, it is possible that mGluR5-expression on classical Hodgkin lymphoma cells not only drives tumor progression, but may also trigger anti-mGluR5 encephalitis already before classical Hodgkin lymphoma-manifestation.
2023-02-10 | GSE212326 | GEO
Project description:The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor with an important role in synaptic function at multiple levels. In physiological conditions, mGluR5 is an essential modulator of synaptic plasticity, learning and memory; whereas in pathological conditions, it is an acknowledged therapeutic target that has been implicated in multiple brain disorders. However, the underlying mechanisms by which mGluR5 acts in these diverse synaptic functions and processes is only partly understood. In this study, we dissected the molecular synaptic modulation mediated by mGluR5 using genetic and pharmacological mouse models to chronically and acutely reduce mGluR5 activity. Using SWATH proteomic analysis, we found that next to dysregulation of synaptic proteins, the major regulation in protein expression in both models concerned specific processes in mitochondria, such as oxidative phosphorylation. Second, we observed morphological alterations in shape and area of specifically postsynaptic mitochondria in mGluR5 KO synapses using electron microscopy. Third, computational and biochemical assays suggested an increase of mitochondrial function in neurons, with increased level of NADP/H and oxidative damage in mGluR5 KO. Altogether, our observations provide diverse lines of evidence of the modulation of synaptic mitochondrial function by mGluR5. This connection suggests a role for mGluR5 as a mediator between synaptic activity and mitochondrial function, a finding which might be a relevant for the improvement of the clinical potential of mGluR5.
2021-08-27 | PXD023809 | Pride
Project description:To try to investigate the mechanism behind the adaptive phenotypes observed in a mice model model of HD crossed with mGluR5 knockout, we analyzed whether mutated huntingtin (Htt) expression in a mGluR5 null background could be altering the expression of genes that might be involved in the pattern of Htt aggregation and HD-related locomotor alterations. In this data set, we include analysis of gene expression in striatum of mice with four different genotypes: HdhQ20/Q20/mGluR5+/+; HdhQ20/Q20/mGluR5-/- ; HdhQ111/Q111/mGluR5+/+ ; HdhQ111/Q111/mGluR5-/-
2013-08-28 | GSE50379 | GEO
Project description:Transcriptome analysis of RETT syndrome conditional mouse model
| PRJNA353961 | ENA
Project description:To try to investigate the mechanism behind the adaptive phenotypes observed in a mice model model of HD crossed with mGluR5 knockout, we analyzed whether mutated huntingtin (Htt) expression in a mGluR5 null background could be altering the expression of genes that might be involved in the pattern of Htt aggregation and HD-related locomotor alterations. In this data set, we include analysis of gene expression in striatum of mice with four different genotypes: HdhQ20/Q20/mGluR5+/+; HdhQ20/Q20/mGluR5-/- ; HdhQ111/Q111/mGluR5+/+ ; HdhQ111/Q111/mGluR5-/- 12 samples were analyzed. We used Partek Genomics Suite v6.5 (Partek, St. Louis, MO) to determine differences in gene expression levels. Genotype effects were considered significant based of the following criteria: (i) ANOVA p-values< 0.05 and (ii) 1.5 fold increase or decrease.
2013-08-28 | E-GEOD-50379 | biostudies-arrayexpress