The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular...

The identification of the Huntington's disease (HD) mutation as a CAG/polyglutamine repeat expansion enabled the generation of transgenic rodent models and gene-targeted mouse models of HD. Of these, mice that are transgenic for an N-terminal huntingtin fragment have been used most extensively because they develop phenotypes with relatively early ages of onset and rapid disease progression. Although the fragment models have led to novel insights into the pathophysiology of HD, it is important that models expressing a mutant version of the full-length protein are analysed in parallel. We have generated congenic C57BL/6 and CBA strains for the HdhQ150 knock-in mouse model of HD so that homozygotes can be analysed on an F1 hybrid background. Although a significant impairment in grip strength could be detected from a very early age, the performance of these mice in the quantitative behavioural tests most frequently used in preclinical efficacy trials indicates that they are unlikely to be useful for preclinical screening using a battery of conventional tests. However, at 22 months of age, the Hdh(Q150/Q150) homozygotes showed unexpected widespread aggregate deposition throughout the brain, transcriptional dysregulation in the striatum and cerebellum and decreased levels of specific chaperones, all well-characterised molecular phenotypes present in R6/2 mice aged 12 weeks. Therefore, when strain background and CAG repeat length are controlled for, the knock-in and fragment models develop comparable phenotypes. This supports the continued use of the more high-throughput fragment models to identify mechanisms of pathogenesis and for preclinical screening.