Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease

Edmond Y W Chan, Ruth Luthi-Carter, Andrew Strand, Steven M Solano, Sarah A Hanson, Molly M DeJohn, Charles Kooperberg, Kathryn O Chase, Marian DiFiglia, Anne B Young, Blair R Leavitt, Jang-Ho J Cha, Neil Aronin, Michael R Hayden, James M Olson

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Abstract

Both transcriptional dysregulation and proteolysis of mutant huntingtin (htt) are postulated to be important components of Huntington's disease (HD) pathogenesis. In previous studies, we demonstrated that transgenic mice that express short mutant htt fragments containing 171 or fewer N-terminal residues (R6/2 and N171-82Q mice) recapitulate many of the mRNA changes observed in human HD brain. To examine whether htt protein length influences the ability of its expanded polyglutamine domain to alter gene expression, we conducted mRNA profiling analyses of mice that express an extended N-terminal fragment (HD46, HD100; 964 amino acids) or full-length (YAC72; 3144 amino acids) mutant htt transprotein. Oligonucleotide microarray analyses of HD46 and YAC72 mice identified fewer differentially expressed mRNAs than were seen in transgenic mice expressing short N-terminal mutant htt fragments. Histologic analyses also detected limited changes in these mice (small decreases in adenosine A2a receptor mRNA and dopamine D2 receptor binding in HD100 animals; small increases in dopamine D1 receptor binding in HD46 and HD100 mice). Neither HD46 nor YAC72 mice exhibited altered mRNA levels similar to those observed previously in R6/2 mice, N171-82Q mice or human HD patients. These findings suggest that htt protein length influences the ability of an expanded polyglutamine domain to alter gene expression. Furthermore, our findings suggest that short N-terminal fragments of mutant htt might be responsible for the gene expression alterations observed in human HD brain.

LanguageEnglish
Pages1939-1951
Number of pages13
JournalHuman Molecular Genetics
Volume11
Issue number17
DOIs
Publication statusPublished - 15 Aug 2002

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Huntington Disease
Gene Expression
Messenger RNA
Aptitude
Transgenic Mice
Amino Acids
Dopamine D1 Receptors
Purinergic P1 Receptors
Dopamine D2 Receptors
Huntingtin Protein
polyglutamine
Brain
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Proteolysis

Keywords

  • animals
  • blotting, northern
  • brain
  • disease models, animal
  • female
  • gene expression profiling
  • humans
  • huntington disease
  • in situ hybridization
  • male
  • mice
  • mice, transgenic
  • molecular sequence data
  • nerve tissue proteins
  • nuclear proteins
  • oligonucleotide array sequence analysis
  • peptides
  • proteins
  • RNA, messenger
  • receptor, adenosine A2A
  • receptors, dopamine D1
  • receptors, dopamine D2
  • receptors, purinergic P1
  • reverse transcriptase polymerase chain reaction

Cite this

Chan, E. Y. W., Luthi-Carter, R., Strand, A., Solano, S. M., Hanson, S. A., DeJohn, M. M., ... Olson, J. M. (2002). Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. Human Molecular Genetics , 11(17), 1939-1951. https://doi.org/10.1093/hmg/11.17.1939
Chan, Edmond Y W ; Luthi-Carter, Ruth ; Strand, Andrew ; Solano, Steven M ; Hanson, Sarah A ; DeJohn, Molly M ; Kooperberg, Charles ; Chase, Kathryn O ; DiFiglia, Marian ; Young, Anne B ; Leavitt, Blair R ; Cha, Jang-Ho J ; Aronin, Neil ; Hayden, Michael R ; Olson, James M. / Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. In: Human Molecular Genetics . 2002 ; Vol. 11, No. 17. pp. 1939-1951.
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Chan, EYW, Luthi-Carter, R, Strand, A, Solano, SM, Hanson, SA, DeJohn, MM, Kooperberg, C, Chase, KO, DiFiglia, M, Young, AB, Leavitt, BR, Cha, J-HJ, Aronin, N, Hayden, MR & Olson, JM 2002, 'Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease' Human Molecular Genetics , vol. 11, no. 17, pp. 1939-1951. https://doi.org/10.1093/hmg/11.17.1939

Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. / Chan, Edmond Y W; Luthi-Carter, Ruth; Strand, Andrew; Solano, Steven M; Hanson, Sarah A; DeJohn, Molly M; Kooperberg, Charles; Chase, Kathryn O; DiFiglia, Marian; Young, Anne B; Leavitt, Blair R; Cha, Jang-Ho J; Aronin, Neil; Hayden, Michael R; Olson, James M.

In: Human Molecular Genetics , Vol. 11, No. 17, 15.08.2002, p. 1939-1951.

Research output: Contribution to journalArticle

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T1 - Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease

AU - Chan, Edmond Y W

AU - Luthi-Carter, Ruth

AU - Strand, Andrew

AU - Solano, Steven M

AU - Hanson, Sarah A

AU - DeJohn, Molly M

AU - Kooperberg, Charles

AU - Chase, Kathryn O

AU - DiFiglia, Marian

AU - Young, Anne B

AU - Leavitt, Blair R

AU - Cha, Jang-Ho J

AU - Aronin, Neil

AU - Hayden, Michael R

AU - Olson, James M

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N2 - Both transcriptional dysregulation and proteolysis of mutant huntingtin (htt) are postulated to be important components of Huntington's disease (HD) pathogenesis. In previous studies, we demonstrated that transgenic mice that express short mutant htt fragments containing 171 or fewer N-terminal residues (R6/2 and N171-82Q mice) recapitulate many of the mRNA changes observed in human HD brain. To examine whether htt protein length influences the ability of its expanded polyglutamine domain to alter gene expression, we conducted mRNA profiling analyses of mice that express an extended N-terminal fragment (HD46, HD100; 964 amino acids) or full-length (YAC72; 3144 amino acids) mutant htt transprotein. Oligonucleotide microarray analyses of HD46 and YAC72 mice identified fewer differentially expressed mRNAs than were seen in transgenic mice expressing short N-terminal mutant htt fragments. Histologic analyses also detected limited changes in these mice (small decreases in adenosine A2a receptor mRNA and dopamine D2 receptor binding in HD100 animals; small increases in dopamine D1 receptor binding in HD46 and HD100 mice). Neither HD46 nor YAC72 mice exhibited altered mRNA levels similar to those observed previously in R6/2 mice, N171-82Q mice or human HD patients. These findings suggest that htt protein length influences the ability of an expanded polyglutamine domain to alter gene expression. Furthermore, our findings suggest that short N-terminal fragments of mutant htt might be responsible for the gene expression alterations observed in human HD brain.

AB - Both transcriptional dysregulation and proteolysis of mutant huntingtin (htt) are postulated to be important components of Huntington's disease (HD) pathogenesis. In previous studies, we demonstrated that transgenic mice that express short mutant htt fragments containing 171 or fewer N-terminal residues (R6/2 and N171-82Q mice) recapitulate many of the mRNA changes observed in human HD brain. To examine whether htt protein length influences the ability of its expanded polyglutamine domain to alter gene expression, we conducted mRNA profiling analyses of mice that express an extended N-terminal fragment (HD46, HD100; 964 amino acids) or full-length (YAC72; 3144 amino acids) mutant htt transprotein. Oligonucleotide microarray analyses of HD46 and YAC72 mice identified fewer differentially expressed mRNAs than were seen in transgenic mice expressing short N-terminal mutant htt fragments. Histologic analyses also detected limited changes in these mice (small decreases in adenosine A2a receptor mRNA and dopamine D2 receptor binding in HD100 animals; small increases in dopamine D1 receptor binding in HD46 and HD100 mice). Neither HD46 nor YAC72 mice exhibited altered mRNA levels similar to those observed previously in R6/2 mice, N171-82Q mice or human HD patients. These findings suggest that htt protein length influences the ability of an expanded polyglutamine domain to alter gene expression. Furthermore, our findings suggest that short N-terminal fragments of mutant htt might be responsible for the gene expression alterations observed in human HD brain.

KW - animals

KW - blotting, northern

KW - brain

KW - disease models, animal

KW - female

KW - gene expression profiling

KW - humans

KW - huntington disease

KW - in situ hybridization

KW - male

KW - mice

KW - mice, transgenic

KW - molecular sequence data

KW - nerve tissue proteins

KW - nuclear proteins

KW - oligonucleotide array sequence analysis

KW - peptides

KW - proteins

KW - RNA, messenger

KW - receptor, adenosine A2A

KW - receptors, dopamine D1

KW - receptors, dopamine D2

KW - receptors, purinergic P1

KW - reverse transcriptase polymerase chain reaction

U2 - 10.1093/hmg/11.17.1939

DO - 10.1093/hmg/11.17.1939

M3 - Article

VL - 11

SP - 1939

EP - 1951

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 17

ER -