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RNAseq analysis of FACS-isolated astrocytes from the striatum of 11-14 month-old knock-in Hdh140 mice after astrocyte-targeted expression of GFAP or JAK2ca

ABSTRACT: We analyzed the transcriptional profile of striatal astrocytes from 1) Hdh140 mice infected with AAV-GFP, 2) astrocytes from Hdh140 mice infected with AAV-JAK2ca (+ AAV-GFP, at the same total virus load). We show that JAK2ca activates the JAK2-STAT3 patwhay in striatal astrocytes, induces reactive changes and activates a proteostasis signature.

ORGANISM(S): Mus musculus

PROVIDER: GSE171141 | GEO | 2022/03/18

REPOSITORIES: GEO

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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.

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RNAseq analysis of FACS-isolated astrocytes from the striatum of 11-14 month-old knock-in Hdh140 mice after astrocyte-targeted expression of GFAP or JAK2ca

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