Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain

Ruth Luthi-Carter, Sarah A Hanson, Andrew D Strand, Donald A Bergstrom, Wanjoo Chun, Nikki L Peters, Annette M Woods, Edmond Y Chan, Charles Kooperberg, Dimitri Krainc, Anne B Young, Stephen J Tapscott, James M Olson

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Pages1911-1926
Number of pages16
JournalHuman Molecular Genetics
Volume11
Issue number17
DOIs
Publication statusPublished - 15 Aug 2002

Fingerprint

Gene Expression
Muscles
Brain
Messenger RNA
Huntington Disease
Corpus Striatum
Tretinoin
Oligonucleotide Array Sequence Analysis
Cerebral Cortex
Cerebellum
Skeletal Muscle
Down-Regulation
polyglutamine
Genes

Keywords

  • animals
  • base sequence
  • blotting, northern
  • blotting, western
  • brain
  • cerebral cortex
  • corpus striatum
  • disease models, animal
  • female
  • gene expression regulation
  • humans
  • huntington disease
  • immunoenzyme techniques
  • male
  • mice
  • mice, transgenic
  • molecular sequence data
  • muscle, skeletal
  • nerve tissue proteins
  • nuclear proteins
  • oligonucleotide array sequence analysis
  • peptides
  • RNA, messenger

Cite this

Luthi-Carter, R., Hanson, S. A., Strand, A. D., Bergstrom, D. A., Chun, W., Peters, N. L., ... Olson, J. M. (2002). Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Human Molecular Genetics , 11(17), 1911-1926. https://doi.org/10.1093/hmg/11.17.1911
Luthi-Carter, Ruth ; Hanson, Sarah A ; Strand, Andrew D ; Bergstrom, Donald A ; Chun, Wanjoo ; Peters, Nikki L ; Woods, Annette M ; Chan, Edmond Y ; Kooperberg, Charles ; Krainc, Dimitri ; Young, Anne B ; Tapscott, Stephen J ; Olson, James M. / Dysregulation of gene expression in the R6/2 model of polyglutamine disease : parallel changes in muscle and brain. In: Human Molecular Genetics . 2002 ; Vol. 11, No. 17. pp. 1911-1926.
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Luthi-Carter, R, Hanson, SA, Strand, AD, Bergstrom, DA, Chun, W, Peters, NL, Woods, AM, Chan, EY, Kooperberg, C, Krainc, D, Young, AB, Tapscott, SJ & Olson, JM 2002, 'Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain' Human Molecular Genetics , vol. 11, no. 17, pp. 1911-1926. https://doi.org/10.1093/hmg/11.17.1911

Dysregulation of gene expression in the R6/2 model of polyglutamine disease : parallel changes in muscle and brain. / Luthi-Carter, Ruth; Hanson, Sarah A; Strand, Andrew D; Bergstrom, Donald A; Chun, Wanjoo; Peters, Nikki L; Woods, Annette M; Chan, Edmond Y; Kooperberg, Charles; Krainc, Dimitri; Young, Anne B; Tapscott, Stephen J; Olson, James M.

In: Human Molecular Genetics , Vol. 11, No. 17, 15.08.2002, p. 1911-1926.

Research output: Contribution to journalArticle

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T1 - Dysregulation of gene expression in the R6/2 model of polyglutamine disease

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AU - Luthi-Carter, Ruth

AU - Hanson, Sarah A

AU - Strand, Andrew D

AU - Bergstrom, Donald A

AU - Chun, Wanjoo

AU - Peters, Nikki L

AU - Woods, Annette M

AU - Chan, Edmond Y

AU - Kooperberg, Charles

AU - Krainc, Dimitri

AU - Young, Anne B

AU - Tapscott, Stephen J

AU - Olson, James M

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N2 - 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.

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KW - blotting, northern

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KW - brain

KW - cerebral cortex

KW - corpus striatum

KW - disease models, animal

KW - female

KW - gene expression regulation

KW - humans

KW - huntington disease

KW - immunoenzyme techniques

KW - male

KW - mice

KW - mice, transgenic

KW - molecular sequence data

KW - muscle, skeletal

KW - nerve tissue proteins

KW - nuclear proteins

KW - oligonucleotide array sequence analysis

KW - peptides

KW - RNA, messenger

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