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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127 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1939-1951
Number of pages13
JournalHuman Molecular Genetics
Issue number17
Publication statusPublished - 15 Aug 2002


  • 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

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