Abstract
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.
Highlights
Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder characterized by involuntary movements, cognitive impairment and psychiatric manifestations
Transgenic mouse models have been generated by inserting into the complete murine genome either a fragment (e.g. R6/2 and N171-82Q models) or a full-length copy (BAC HD and YAC HD models) of the human huntingtin gene carrying an abnormal expansion of the CAG repeat tract [5,6]
KI mouse models carry expanded CAG repeats contained within the native murine huntingtin gene [7,8] such that KI models more closely mimic the genetic context of patients with HD
Summary
Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder characterized by involuntary movements, cognitive impairment and psychiatric manifestations. Since the identification of the mutation responsible for the disease, numerous mouse models have been generated to investigate disease pathogenesis and therapeutic approaches preclinically, with all these models carrying an abnormal expansion of the CAG-repeat stretch derived from the human huntingtin gene. Transgenic mouse models have been generated by inserting into the complete murine genome either a fragment (e.g. R6/2 and N171-82Q models) or a full-length copy (BAC HD and YAC HD models) of the human huntingtin gene carrying an abnormal expansion of the CAG repeat tract [5,6]. KI mouse models carry expanded CAG repeats contained within the native murine huntingtin gene [7,8] such that KI models more closely mimic the genetic context of patients with HD. KI models may contain either expanded CAG repeats within an unmodified murine gene (e.g. Hdh(CAG(150))) or a chimeric human/mouse exon 1 carrying the expanded CAG repeat region and the human polyproline region (e.g. CAG 71, CAG 94, CAG 140, and the zQ175 model described here)
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