Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA217365 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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
Project description:Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. Gene expression profiles were analyzed to examine the effects of p62 depletion in mouse with or without mutant huntingtin exon 1 To examine the effect of p62 depletion on the transcriptome of Huntington's disease model mice, we crossed p62 knockout mice with HD model mice. We extracted total RNA from the striatum of these mice at 8 weeks and used for a microaaray analysis. The samples are HD transgenic mice with p62 knockout (HD_p62KO), HD mice with normal p62 (HD_p62WT), non-HD-transgenic mice with p62 knockout (NT_p62KO), and non-HD-transgenic mice with normal p62 (NT_p62WT).
2014-10-10 | E-GEOD-62210 | biostudies-arrayexpress
Project description:Evaluation of transcriptional changes in the striatum may be an effective approach to understanding the natural history of changes in expression contributing to the pathogenesis of Huntington disease (HD). We have performed genome-wide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age using two platforms in parallel; Affymetrix and Illumina. We performed gene expression profiling on the same striatal mRNA across both platforms.
2010-01-31 | GSE18551 | GEO
Project description:Evaluation of transcriptional changes in the striatum may be an effective approach to understanding the natural history of changes in expression contributing to the pathogenesis of Huntington disease (HD). We have performed genome-wide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age using two platforms in parallel; Affymetrix and Illumina. We performed gene expression profiling on the same striatal mRNA across both platforms. Keywords: time course,disease state analysis
2010-01-31 | GSE19676 | GEO
Project description:Alterations to corticostriatal glutamatergic function are early pathophysiological changes associated with Huntington?s disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD.
2017-12-05 | GSE104990 | GEO
Project description:Striato nigral circuit is composed of medium spiny neuronal projections that were mainly sent from striatum to midbrain substantial nigra (SN), which is essential for regulating motor behaviors. Dysfunction of striato-nigral circuitry may cause a series of motor disabilities which are associated with neurodegenerative disorders, such as Huntington disease (HD). Although the etiology of HD is known as abnormally expanded CAG repeats of the huntingtin gene (HTT), treatment of HD remains tremendous challenges. One possible reason is lack of effective HD model which resembles striato nigral circuitry deficits for the pharmacology studies. Here we first differentiate striatum-like organoids from human pluripotent stem cells, containing functional medium spiny neurons (MSN). We then generated 3D striato nigral circuitoids by assembling striatum-like organoids with midbrain substantial nigra like organoids. With AVV hSYN GFP viral tracing, the extensive MSN projections from striatum to SN are established, which form synaptic connection with dopaminergic neurons and showed the electronic field potentials by labeling striatum like organoids with optogenetic virus. Furthermore, this striato nigral circuitoids exhibited improved calcium activity than individual striatal organoids. Importantly, we further demonstrated the reciprocal projection defects of the HD iPSC derived circuitoids, which could be reversed with the treatment of brain derived nerve factors. Altogether, the striato nigral circuitoids could be used for identifying MSN projection defects, which would be applied as a potential drug test platform for HD.
2024-05-06 | GSE251684 | GEO
Project description:Huntington neurodegenerative disease (HD) is associated with extensive down-regulation of neuronal genes. We show preferential down-regulation of super-enhancer-regulated neuronal function genes in the striatum of HD mice. Striatal super-enhancers display extensive H3K27 acetylation within gene bodies and drive transcription characterized by low levels of paused RNAPII. Down-regulation of gene expression is associated with diminished H3K27 acetylation and RNAPII recruitment. Striatal super-enhancers are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Thus, enhancer topography and transcription dynamics are major parameters determining the propensity of a gene to be deregulated in a neurodegenerative disease. Examination of H3k27ac and RNA pol II in Striatum by deep sequencing
2015-04-01 | E-GEOD-59570 | biostudies-arrayexpress
Project description:We generated two types of DNA methylation datasets (Reduced Representation Bisulfite Sequencing [RRBS] and custom methylation array) from a heterozygous HD knock-in mouse model. The heterozygous Htt knock-in line expressed one wildtype endogenous Htt allele and a second Htt allele with knock-in of human mHTT exon 1 with either approximately 190 CAG repeats (Q175) or 20 CAG repeats (Q20). For each genotype (Q175 and Q20) we analyzed two brain regions (striatum and cerebellum) from 8 mice each on the RRBS platform (N=32 RRBS samples). Our EWAS of mutant Htt gene status (i.e. Q175 status) across the two brain regions identified two genome-wide significant CpGs in Htt region. contributor: CHDI foundation
2020-07-02 | GSE147156 | GEO
Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.
2010-04-08 | E-GEOD-21237 | biostudies-arrayexpress