Human Molecular Genetics, 2002, Vol. 11, No. 17 1911-1926
© 2002 Oxford University Press
Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain
1Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital, Charlestown, MA 02129-4404, USA, 2Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA and 3Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5H 4H4.
Received March 12, 2002; Accepted June 24, 2002
Previous analyses of gene expression in a mouse model of Huntington's disease (R6/2) indicated that an N-terminal fragment of mutant huntingtin causes downregulation of striatal signaling genes and particularly those normally induced by cAMP and retinoic acid. The present study expands the regional and temporal scope of this previous work by assessing whether similar changes occur in other brain regions affected in Huntington's disease and other polyglutamine diseases and by discerning whether gene expression changes precede the appearance of disease signs. Oligonucleotide microarrays were employed to survey the expression of 
11 000 mRNAs in the cerebral cortex, cerebellum and striatum of symptomatic R6/2 mice. The number and nature of gene expression changes were similar among these three regions, influenced as expected by regional differences in baseline gene expression. Time-course studies revealed that mRNA changes could only reliably be detected after 4 weeks of age, coincident with development of early pathologic and behavioral changes in these animals. In addition, we discovered that skeletal muscle is also a target of polyglutamine-related perturbations in gene expression, showing changes in mRNAs that are dysregulated in brain and also muscle-specific mRNAs. The complete dataset is available at www.neumetrix.info.
* To whom correspondence should be addressed at: Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA 98109, USA. Tel: +1 2066677955; Fax: +1 2066672917; Email: jolson{at}fhcrc.org
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