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.

Détails

ID Serval
serval:BIB_89FF857F0D32
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
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.
Périodique
Human Molecular Genetics
Auteur(s)
Kuhn A., Goldstein D.R., Hodges A., Strand A.D., Sengstag T., Kooperberg C., Becanovic K., Pouladi M.A., Sathasivam K., Cha J.H., Hannan A.J., Hayden M.R., Leavitt B.R., Dunnett S.B., Ferrante R.J., Albin R., Shelbourne P., Delorenzi M., Augood S.J., Faull R.L., Olson J.M., Bates G.P., Jones L., Luthi-Carter R.
ISSN
0964-6906 (Print)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
2007
Volume
16
Numéro
15
Pages
1845-1861
Langue
anglais
Résumé
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.
Mots-clé
Animals, Brain/metabolism, Brain/pathology, Corpus Striatum/metabolism, Disease Models, Animal, Gene Dosage, Gene Expression, Humans, Huntington Disease/genetics, Huntington Disease/metabolism, Mice, Mice, Mutant Strains, Mutation, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Neurons/metabolism, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Phenotype, RNA, Messenger/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
22/04/2013 9:12
Dernière modification de la notice
08/05/2019 21:38
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