Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175

PLoS One. 2012;7(12):e49838. doi: 10.1371/journal.pone.0049838. Epub 2012 Dec 20.


Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest that the zQ175 knock-in line could be a suitable model for the evaluation of therapeutic approaches and early events in the pathogenesis of HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal* / radiation effects
  • Body Weight / genetics
  • Cognition / physiology
  • Darkness
  • Disease Models, Animal*
  • Female
  • Gene Knock-In Techniques*
  • Genetic Markers / genetics
  • Hand Strength / physiology
  • Heterozygote
  • Homozygote
  • Huntington Disease / genetics*
  • Huntington Disease / physiopathology
  • Male
  • Mice
  • Neostriatum / metabolism
  • Nerve Tissue Proteins / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repetitive Sequences, Nucleic Acid
  • Rotarod Performance Test
  • Survival Analysis
  • Transcription, Genetic / genetics


  • Genetic Markers
  • Nerve Tissue Proteins
  • RNA, Messenger

Grant support

CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington’s disease. The research described was conducted by PsychoGenics under a fee-for-service agreement for CHDI Foundation in collaboration with and funded by CHDI Foundation. The funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript. CHDI Foundation has recently provided financial support to the Public Library of Science for PLOS Currents: Huntington Disease.