Huntington’s disease (HD) is an autosomal-dominantly inherited, fatal, neurodegenerative disorder. Patients present with motor dysfunctions, psychiatric symptoms, cognitive impairments, and metabolic abnormalities. HD is solely caused by the expansion of an unstable repeat of CAG base triplets in the coding region of the Huntingtin gene, HTT. The age of disease onset correlates inversely with the CAG repeat length and starts at the age of 40–50 years.
Next to the rodent models R6/2 mice and BACHD rats, Scantox now also offers the zQ175DN-KI mouse model to test new compounds for their in vivo efficacy. In these zQ175DN-KI mice, the murine HTT exon 1 is replaced by the human HTT exon 1 sequence with 180-220 CAG repeats. Furthermore, the neo cassette of these KI mice is deleted (DN).
First in-house evaluations of zQ175DN-KI mice showed that mutant HTT (mHTT) are highly expressed in the isocortex of 5.5 months old animals (Figure 1A) while the body weight was significantly reduced at the age of 23 weeks, although first body weight effects were already visible at the age of 12 weeks (Figure 1B). Evaluation of behavioral deficits showed that zQ175DN-KI mice present significant deficits in the nest building and beam walk test as shown by a reduced nest building score and increased number of slips on a 10 mm square beam, respectively (Figure 2A and B).
These preliminary results suggest, that the knockin of the mutant human HTT gene in zQ175DN-KI mice results in highly increased mHTT levels causing a reduced body weight already at early age and severely reduced general health and motor skills at the age of 5.5 months.
zQ175DN-KI mice are thus a valuable tool to test your new compounds against Huntington’s disease.
Figure 1: Quantification of mHTT and body weight of 5.5 months old mixed sex zQ175DN KI and wild type mice. A: mHTT quantification in the isocortex by sandwich immunosorbent assay using the MesoScale Discovery platform. WT: n = 3; zQ175DN KI: n = 12. Mean + SEM. Unpaired t-test. B: Body weight progression. n = 12 per group. Mean ± SEM; repeated measures two-way ANOVA with Sidak’s multiple comparison post hoc test; analysis of body weight progression was significant by Tukey’s multiple comparison post hoc test for both genotypes (not labeled). *p<0.05; ***p<0.001. mHTT: mutant huntingtin; WT: wild type.
Figure 2. Nest building and beam walk of 5.5 months old mixed sex zQ175DN KI and WT mice. A: Nest building score of 1 representing a poor nest and score of 5 representing a perfect nest. B: Number of slips on a 10 mm square beam. n = 12 per group. Mean + SEM; Mann-Whitney U-test (A) or unpaired t-test (B). **p<0.01.***p<0.001.
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