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

doi:10.1093/hmg/11.17.1911

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

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

328 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1911-1926
Number of pages	16
Journal	Human Molecular Genetics
Volume	11
Issue number	17
DOIs	https://doi.org/10.1093/hmg/11.17.1911
Publication status	Published - 15 Aug 2002

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

Access to Document

10.1093/hmg/11.17.1911

Cite this

Luthi-Carter, R., Hanson, S. A., Strand, A. D., Bergstrom, D. A., Chun, W., Peters, N. L., Woods, A. M., Chan, E. Y., Kooperberg, C., Krainc, D., Young, A. B., Tapscott, S. J., & 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

@article{8155e52fb0a34829920982466adc8b90,

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.",

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",

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

year = "2002",

month = aug,

day = "15",

doi = "10.1093/hmg/11.17.1911",

language = "English",

volume = "11",

pages = "1911--1926",

journal = "Human Molecular Genetics ",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

}

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

TY - JOUR

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

T2 - parallel changes in muscle and brain

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

PY - 2002/8/15

Y1 - 2002/8/15

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.

AB - 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.

KW - animals

KW - base sequence

KW - blotting, northern

KW - blotting, western

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

U2 - 10.1093/hmg/11.17.1911

DO - 10.1093/hmg/11.17.1911

M3 - Article

C2 - 12165554

SN - 0964-6906

VL - 11

SP - 1911

EP - 1926

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 17

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this