title: Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain.
abstract: 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 approximately 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.
authors.affiliation: Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital, Charlestown, MA 02129-4404, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Hanson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Strand
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bergstrom
authors.forename: Wanjoo
authors.initials: W
authors.lastname: Chun
authors.forename: Nikki L
authors.initials: NL
authors.lastname: Peters
authors.forename: Annette M
authors.initials: AM
authors.lastname: Woods
authors.forename: Edmond Y
authors.initials: EY
authors.lastname: Chan
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; C097188:polyglutamine