Select Page

A. KUDWA, J. TORELLO, J. FITZPATRIC, S. MILLER, R. MUSHLIN, L. PARK , D. HOWLAND, S. RAMBOZ, L. MENALLED

Huntington’s Disease (HD) is an autosomal dominant inherited disease characterized by an abnormal and unstable expansion in the number of CAG trinucleotide repeats in exon 1 of the huntingtin gene (Group HsDCR, 1993). HD is characterized by motor, psychiatric and cognitive symptoms, and the longer the CAG repeat, the earlier the onset of symptoms. Numerous mouse models have been generated to examine the pathogenesis of the disease and to evaluate therapeutic approaches, but the most precise genetic reproductions of the human condition are the knock-in (KI) mouse models which express the huntingtin mutation in the proper genetic and protein context on the murine gene. Furthermore, the heterozygous knock in mouse serves as a better animal model of the human disorder, as compared to the homozygous mouse, given that Huntington disease homozygosity is very rare in humans. The CAG 140 KI mouse model carries a chimeric mouse/human exon 1 containing around 125 CAG repeats and the human polyproline region inserted in the murine huntingtin gene. Motor abnormalities displayed by CAG 140 HOMO KI mice on the accelerating rotarod task are detected from as early as 4 months, but are not observed in CAG 140 HET KI mice until 11 months of age (Rising et al., 2011). Recently, spontaneous expansion of the CAG repeat stretch in the CAG 140 KI mouse model has led to a new KI line carrying around 190 CAG repeats (CAG 175 KI). We have shown that CAG 175 HOMO KI mice show a hypoactive phenotype from as early as 8 weeks of age, and while there was a delay in onset, a hypoactive phenotype was also observed in CAG 175 HET KI mice from 4-5 months of age. As described in HdhQ200KI and HdhQ150 KI mice, the balance beam test proves to be a sensitive measure of motor impairment, detecting motor deficits at 50 and 100 weeks of age, respectively (Heng et al., 2007 and 2010). The current study compares findings from both CAG 140 KI and CAG 175 KI mice using the tapered balance beam task, with an emphasis on evaluating whether early deficits can be revealed in heterozygous KI mice. Detection of early motor deficits, together with the genetic similarities to the human condition, would further support the use of heterozygous knock in mice as a tool for examining the early mechanisms of pathophysiology of HD and for screening potential treatments. This research was supported by the CHDI Foundation.