Human Molecular Genetics Advance Access published online on May 21, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm133
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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
1 Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland 2 National Center of Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research (ISREC) and Swiss Institute of Bioinformatics (SIB) 1066 Epalinges, Switzerland 3 Depts. of Psychological Medicine and Medical Genetics, Wales College of Medicine and School of Biosciences, Cardiff Univ., Heath Park, Cardiff CF14 4XN, Wales, UK 4 Dept. of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, UK 5 Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA 6 Department of Medical Genetics, University of British Columbia, and Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, BC, V5Z 4H4 Canada 7 Dept. of Medical and Molecular Genetics, King's College London School of Medicine, London SE1 9RT, UK 8 MassGeneral Institute of Neurodegenerative Disease (MIND), Massachusetts General Hospital, Charlestown, MA 02129, USA 9 University Laboratory of Physiology, Oxford OX13PT, UK and Howard Florey Institute, National Neuroscience Facility, Univ. of Melbourne, VIC 3010, Australia 10 Bedford Veterans Affairs Medical Center and Depts. of Neurology, Pathology, and Psychiatry, Boston Univ. School of Medicine, Bedford, MA 07130, USA 11 Geriatrics Research, Education, and Clinical Center, Ann Arbor Veterans Affairs Medical Center and Dept. of Neurology, Univ. of Michigan, USA 12 Div. of Molecular Genetics, Faculty of Biomedical and Life Sciences, Univ. of Glasgow, Glasgow G11 6NU, Scotland, UK 13 Dept. of Anatomy with Radiology, Univ. of Auckland, Private Bag 92019, Auckland, NZ
* Corresponding author: Ecole Polytechnique Fédérale de Lausanne (EPFL), AI 2138, Station 15, 1015 Lausanne, Switzerland; Tel: +41 21 693 9533; Fax: +41 21 693 9628; Email: ruth.luthi-carter{at}epfl.ch
Received April 17, 2007; Revised May 10, 2007; Accepted May 10, 2007
In order to test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared mRNA changes 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-month and 22-month CHL2Q150/Q150, 18-month HdhQ92/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 to those caused by 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.
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