Transcription profiling of mouse striatum from 12 weeks-old R6/2 vs. control animals
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Alexandre Kuhn
PROVIDER: E-GEOD-9857 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.
Kuhn Alexandre A Goldstein Darlene R DR Hodges Angela A Strand Andrew D AD Sengstag Thierry T Kooperberg Charles C Becanovic Kristina K Pouladi Mahmoud A MA Sathasivam Kirupa K Cha Jang-Ho J JH Hannan Anthony J AJ Hayden Michael R MR Leavitt Blair R BR Dunnett Stephen B SB Ferrante Robert J RJ Albin Roger R Shelbourne Peggy P Delorenzi Mauro M Augood Sarah J SJ Faull Richard L M RL Olson James M JM Bates Gillian P GP Jones Lesley L Luthi-Carter Ruth R
Human molecular genetics 20070521 15
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 bra ...[more]
Similar Datasets
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.
2008-06-16 | E-GEOD-9803 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series:; GSE9375: Striatal gene expression data from 12 months-old Hdh4/Q80 mice and control mice. GSE9857: Striatal gene expression data from 12 weeks-old R6/2 mice and control mice; GSE10202: Striatal gene expression data from 22-month-old CHL2 mice and control mice. Experiment Overall Design: Refer to individual Series
2008-05-21 | E-GEOD-10263 | 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 3 Hdh4/Q80 mutant mice (12 months-old) and 3 age-matched wild-type littermates.
2008-06-16 | E-GEOD-9375 | biostudies-arrayexpress
Project description:Achieving a mechanistic understanding of disease and initiating preclinical therapeutic trials necessitate the study of huntingtin toxicity and its remedy in model systems. To allow the engagement of appropriate experimental paradigms, Huntingtonâs disease (HD) models need to be validated in terms of how they recapitulate a particular aspect of human disease. In order to examine transcriptome-related effects of mutant huntingtin, we compared striatal mRNA profiles from seven genetic mouse models of disease to that of postmortem human HD caudate using microarray analysis. 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 models of HD took longer to appear, 15-month and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. When the affected genes were compared across models, a robust concordance was observed. Importantly, changes concordant across multiple lines mice were also in excellent agreement with the mRNA changes seen in human HD caudate. Although it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared to those caused by expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. There was, however, an overall concordance between transcriptomic signature and disease stage. We thus conclude that the transcriptional changes of HD can be modelled in several available lines of transgenic mice, comprising lines expressing both N-terminal and full-length mutant huntingtin proteins. The combined analysis of mouse and human HD transcriptomes provides an important chronology of mutant huntingtin's gene expression effects. Experiment Overall Design: Striatal samples from 6 Q92 mutant mice (3 3-month-old and 3 18-month-old) and 6 age-matched wild-type mice.
2008-06-15 | E-GEOD-7958 | biostudies-arrayexpress
Project description:Achieving a mechanistic understanding of disease and initiating preclinical therapeutic trials necessitate the study of huntingtin toxicity and its remedy in model systems. To allow the engagement of appropriate experimental paradigms, Huntingtonâs disease (HD) models need to be validated in terms of how they recapitulate a particular aspect of human disease. In order to examine transcriptome-related effects of mutant huntingtin, we compared striatal mRNA profiles from seven genetic mouse models of disease to that of postmortem human HD caudate using microarray analysis. 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 models of HD took longer to appear, 15-month and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. When the affected genes were compared across models, a robust concordance was observed. Importantly, changes concordant across multiple lines mice were also in excellent agreement with the mRNA changes seen in human HD caudate. Although it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared to those caused by expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. There was, however, an overall concordance between transcriptomic signature and disease stage. We thus conclude that the transcriptional changes of HD can be modelled in several available lines of transgenic mice, comprising lines expressing both N-terminal and full-length mutant huntingtin proteins. The combined analysis of mouse and human HD transcriptomes provides an important chronology of mutant huntingtin's gene expression effects. Experiment Overall Design: Striatal samples from 4 CHL2 Q150/Q150 mutant mice and 4 age-matched wild-type mice.
2008-04-10 | E-GEOD-10202 | biostudies-arrayexpress
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
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
2011-10-13 | GSE1980 | GEO
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
2011-10-12 | E-GEOD-1980 | biostudies-arrayexpress
Project description:Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 9 weeks old WT (n=9), R6/2 (n=9), HDAC4het (n=9) and Double R6/2::HDAC4het (n=10) mice. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).
2014-10-10 | E-GEOD-38218 | biostudies-arrayexpress