Six-week-old R6/2 HD mouse striatum
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE1980 | GEO | 2011/10/13
SECONDARY ACCESSION(S): PRJNA90411
REPOSITORIES: GEO
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Project description:Wild-type CBAxC57BL/6 (6 weeks of age) and HD Exon 1 R6/2 CBAxC57BL/6 (6 weeks of age). Control groups for two drug studies. All animals injected with normal saline 30-60 minutes prior to sacrifice. Keywords: parallel sample
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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.
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Project description:To characterize the epigenome of R6/1 HD mice in specific striatal cellular populations
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Project description:To characterize the epigenome of HD R6/1 mice in striatal cells using CUT&TAG on neuronal and non-neuronal nuclei
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Project description:Huntington’s disease is a genetic disease caused by a single mutation. It is characterised by progressive movement, emotional and cognitive deficits. R6/2 transgenic mice carrying the Huntington’s disease mutation have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up- or down-regulated in untreated R6/2 mice had returned towards normal levels after treatment. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated. Keywords = HD Keywords = Huntingtin Keywords = cognitive disorder Keywords = R6/2 Keywords = transgenic mice Keywords = gene expression Keywords = microarray Keywords: ordered
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Project description:To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials. Experiment Overall Design: Striatal samples from 5 R6/2 mutant mice (12 weeks-old) and 4 age-matched wild-type mice.
2008-06-16 | E-GEOD-9804 | biostudies-arrayexpress
Project description:To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials. Experiment Overall Design: Striatal samples from 4 R6/2 mutant mice (12 weeks-old) and 5 age-matched wild-type mice.
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Project description:HD R6/1 transgenic mouse line brain hemispheres dissected. RNA targets were created for transgenics and wildtypes at time points 18, 22 and 27 weeks. Profiles and data analysis performed using the Bioconductor software and linear model contrasts using LIMMA on RMA probeset summarys. Experiment Overall Design: 18 samples extracted, 3 transgenic plus 3 littermate controls analysed at each timepoint.
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