Analysis of differential gene expression in the striatum of R6/2 Huntington's disease model vs. control mice
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PROVIDER: PRJNA430856 | ENA |
REPOSITORIES: ENA
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Project description:A challenge in treating Huntington's disease (HD) is the complexity of affected brain regions and cell types. We carried out a systematic analysis of cell type-specific changes in cortex and striatum from R6/2 mice at 8 and 12w, and discovered major expression changes in oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs), suggesting that many OLs were arrested in an immature state. Causal gene network analysis implicates PRKCE and SWI/SNF in abnormal OL maturation. PRKCE protein was dramatically decreased. Disrupted cell-to-cell signaling between medium spinyneurons and OL that may contribute to neuronal dysfunction was identified in R6/2 mice using ligand-receptor analysis. These findings reveal novel insights into OL pathology, span multiple brain regions in humans and mice and suggest therapeutic strategies.
2022-11-14 | GSE180294 | GEO
Project description:5 mice per group of each: R6/2 and isogenic wild-type controls.
2020-01-30 | GSE109416 | GEO
Project description:Gene expression profiling of striatum in R6/2 Huntington’s disease (HD) model mouse. Striatum gene set contained gene expression alterations in other neuronal populations, such as oligodendrocyte, astrocyte, microglia and interneuron.
2020-06-03 | GSE113929 | GEO
Project description:We investigated gene expression signatures in the striatum of wild-type mice injected with a control/scrambeled LNA-oligonucleotide (LNA-SCB) and R6/2 mice injected with LNA-SCB or LNA-CTG. Five mice were used per condition. Each group of mice received two consecutive intrastriatal injections of LNA-CTG or LNA-SCB (0.05 nmols per injection, separated by 3 days) at 11 weeks of age , when motor symptoms appeared in the R6/2 mice. Injection of LNA-CTG resulted in a signifficant attenuation of the R6/2 mice motor defficits, as early as one week after administration (12 weeks of age) and persisted for at least 4 additional weeks (15 weeks of age). Overal gene expression in each group was evaluated short before motor improvement was observed (5 days post-injection), to detect gene expression changes and signalling pathway alterations underlying the benefficial effects. Gene expression was assessed with Agilent SurePrint G3 Mouse GE 8 × 60K Microarray. Target genes were validated using real-time quantitative PCR.
2017-01-01 | GSE85126 | GEO
Project description:Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.
2016-02-01 | GSE48104 | GEO
Project description:Gene expression profiling of striatum in Huntington's disease model mouse
| PRJNA454481 | ENA
Project description:Transcriptional dysregulation is an early feature of Huntington's disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. mRNA-seq in wild type and R6/2 cortex and striatum at 8 and 12 weeks.
2013-07-18 | E-GEOD-48962 | biostudies-arrayexpress
Project description:Transcriptional dysregulation is an early feature of Huntington's disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. ChIP-seq for H3K4me3 in wild type and R6/2 cortex and striatum at 8 and 12 weeks.
2013-07-18 | E-GEOD-48960 | biostudies-arrayexpress
Project description:Using the Cross-linking immuno-precipitation (CLIP) methodology combined with high throughput sequencing analysis, we have identified the RNA targets of the RNA-binding protein RBM5 in the brain of wild-type and R6/2 (Huntington's disease model) adult mice. In parallel, transcriptome analysis was performed by RNA-sequencing using brain samples from the same animals.
2023-06-22 | GSE187445 | GEO
Project description:Animal models play a critical role in the study of Huntington’s disease (HD), for example to elucidate underlying molecular mechanisms or to develop novel therapeutic venues. One of the first transgenic mouse models of HD, the R6/2 line, has been described in 1996 and has since become one of the most studied models of the disease (Mangiarini et al. 1996; Li, Popovic & Brundin 2005). R6/2 mice express the human exon 1 under control of the human huntingtin promoter at around 75% of the endogenous levels. The expression of the exon 1 with a CAG repeat length of around 115 evokes rapid disease progression and animals display multiple HD-associated neuropathological changes. First signs of disease can occur as early as three weeks and mice are severely impaired by the age of 8-12 weeks. The expected life span is 13-16 weeks (Li, Popovic & Brundin 2005). Here we were interested in the changes occurring in the proteomic landscape as well as in phosphoproteomic signaling networks in the R6/2 mouse model as compared to wild type mice. To this end, we performed comprehensive quantitative phosphoproteome and proteome analyses of striatum of one, two, and three months old mice of both genotypes. A total of nine or more samples per group was analyzed according to the experimental layout shown above. To allow for accurate quantification, peptides of each sample were labelled using tandem mass tags (TMT) and replicates of different conditions were combined. Each combined sample contained an aliquot of a pooled sample consisting of 12 sample lysates. This pooled sample was intended to serve as a reference to allow for quantitative comparison between all combined samples.
2019-06-03 | PXD013771 | Pride