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

Alexandre Kuhn, Darlene R. Goldstein, Angela Hodges, Andrew D. Strand, Thierry Sengstag, Charles Kooperberg, Kristina Becanovic, Mahmoud A. Pouladi, Kirupa Sathasivam, Jang Ho J Cha, Anthony J. Hannan, Michael R. Hayden, Blair R. Leavitt, Stephen B. Dunnett, Robert J. Ferrante, Roger Albin, Peggy Shelbourne, Mauro Delorenzi, Sarah J. Augood, Richard L M FaullJames M. Olson, Gillian P. Bates, Lesley Jones, Ruth Luthi-Carter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

279 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1845-1861
Number of pages17
JournalHuman Molecular Genetics
Volume16
Issue number15
DOIs
Publication statusPublished - 1 Aug 2007
Externally publishedYes

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