Human Molecular Genetics Advance Access originally published online on May 21, 2007
Human Molecular Genetics 2007 16(15):1845-1861; doi:10.1093/hmg/ddm133
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Departments of Psychological Medicine and Medical Genetics, Wales College of Medicine and School of Biosciences, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK, 4 Department 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 Department 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 OX1 3PT, UK and Howard Florey Institute, National Neuroscience Facility, University of Melbourne, VIC 3010, Australia, 10 Bedford Veterans Affairs Medical Center and Departments of Neurology, Pathology, Psychiatry, Boston University School of Medicine, Bedford, MA 07130 USA, 11 Geriatrics Research, Education, and Clinical Center, Ann Arbor Veterans Affairs Medical Center and Department of Neurology, University of Michigan, USA, 12 Division of Molecular Genetics, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 6NU, Scotland, UK, 13 Department of Anatomy with Radiology, University of Auckland, Private Bag 92019, Auckland, New Zealand and
* To whom correspondence should be addressed at: Ecole Polytechnique Fédérale de Lausanne (EPFL), AI 2138, Station 15, 1015 Lausanne, Switzerland. Tel: +41 216939533; Fax: +41 216939628; Email: ruth.luthi-carter{at}epfl.ch
Received April 17, 2007; Accepted May 10, 2007
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 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 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Zabel, L. Mao, B. Woodman, M. Rohe, M. A. Wacker, Y. Klare, A. Koppelstatter, G. Nebrich, O. Klein, S. Grams, et al. A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease Mol. Cell. Proteomics, April 1, 2009; 8(4): 720 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. B. Brown, A. I. Bogush, and M. E. Ehrlich Neocortical expression of mutant huntingtin is not required for alterations in striatal gene expression or motor dysfunction in a transgenic mouse Hum. Mol. Genet., October 15, 2008; 17(20): 3095 - 3104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Benn, T. Sun, G. Sadri-Vakili, K. N. McFarland, D. P. DiRocco, G. J. Yohrling, T. W. Clark, B. Bouzou, and J.-H. J. Cha Huntingtin Modulates Transcription, Occupies Gene Promoters In Vivo, and Binds Directly to DNA in a Polyglutamine-Dependent Manner J. Neurosci., October 15, 2008; 28(42): 10720 - 10733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Thomas, G. Coppola, P. A. Desplats, B. Tang, E. Soragni, R. Burnett, F. Gao, K. M. Fitzgerald, J. F. Borok, D. Herman, et al. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice PNAS, October 7, 2008; 105(40): 15564 - 15569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Runne, E. Regulier, A. Kuhn, D. Zala, O. Gokce, V. Perrin, B. Sick, P. Aebischer, N. Deglon, and R. Luthi-Carter Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry J. Neurosci., September 24, 2008; 28(39): 9723 - 9731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. McLear, D. Lebrecht, A. Messer, and W. J. Wolfgang Combinational approach of intrabody with enhanced Hsp70 expression addresses multiple pathologies in a fly model of Huntington's disease FASEB J, June 1, 2008; 22(6): 2003 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Doi, K. Okamura, P. O. Bauer, Y. Furukawa, H. Shimizu, M. Kurosawa, Y. Machida, H. Miyazaki, K. Mitsui, Y. Kuroiwa, et al. RNA-binding Protein TLS Is a Major Nuclear Aggregate-interacting Protein in Huntingtin Exon 1 with Expanded Polyglutamine-expressing Cells J. Biol. Chem., March 7, 2008; 283(10): 6489 - 6500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lim, L. Fedrizzi, M. Tartari, C. Zuccato, E. Cattaneo, M. Brini, and E. Carafoli Calcium Homeostasis and Mitochondrial Dysfunction in Striatal Neurons of Huntington Disease J. Biol. Chem., February 29, 2008; 283(9): 5780 - 5789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarkar, G. Krishna, S. Imarisio, S. Saiki, C. J. O'Kane, and D. C. Rubinsztein A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin Hum. Mol. Genet., January 15, 2008; 17(2): 170 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Strand, Z. C. Baquet, A. K. Aragaki, P. Holmans, L. Yang, C. Cleren, M. F. Beal, L. Jones, C. Kooperberg, J. M. Olson, et al. Expression Profiling of Huntington's Disease Models Suggests That Brain-Derived Neurotrophic Factor Depletion Plays a Major Role in Striatal Degeneration J. Neurosci., October 24, 2007; 27(43): 11758 - 11768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Y. Heng, S. J. Tallaksen-Greene, P. J. Detloff, and R. L. Albin Longitudinal Evaluation of the Hdh(CAG)150 Knock-In Murine Model of Huntington's Disease J. Neurosci., August 22, 2007; 27(34): 8989 - 8998. [Abstract] [Full Text] [PDF]
|
|