Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse striatum from 3- and 18-month-old Q92 vs. control animals

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Alexandre Kuhn

PROVIDER: E-GEOD-7958 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

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]

PMID: 17519223

Similar Datasets

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.

Dataset Information

Transcription profiling of mouse striatum from 3- and 18-month-old Q92 vs. control animals

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets