Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease

Abstract

An expanded CAG repeat is the underlying genetic defect in Huntington disease, a disorder characterized by motor, psychiatric and cognitive deficits and striatal atrophy associated with neuronal loss. An accurate animal model of this disease is crucial for elucidation of the underlying natural history of the illness and also for testing experimental therapeutics. We established a new yeast artificial chromosome (YAC) mouse model of HD with the entire human HD gene containing 128 CAG repeats (YAC128) which develops motor abnormalities and age-dependent brain atrophy including cortical and striatal atrophy associated with striatal neuronal loss. YAC128 mice exhibit initial hyperactivity, followed by the onset of a motor deficit and finally hypokinesis. The motor deficit in the YAC128 mice is highly correlated with striatal neuronal loss, providing a structural correlate for the behavioral changes. The natural history of HD-related changes in the YAC128 mice has been defined, demonstrating the presence of huntingtin inclusions after the onset of behavior and neuropathological changes. The HD-related phenotypes of the YAC128 mice show phenotypic uniformity with low inter-animal variability present, which together with the age-dependent striatal neurodegeneration make it an ideal mouse model for the assessment of neuroprotective and other therapeutic interventions.

Mouse models of Huntington's disease

“…Weight loss, however, might also be an undesirable side effect of a specific treatment and needs to be reported when observed. As mentioned above, most of the full-length transgenic HD mouse models, such as BAC HD and YAC128, present significantly increased body weight (Gray et al, 2008;Slow et al, 2003), which has been found to negatively impact rotarod performance and locomotor activity assessments (body weight curves of the BAC HD line are shown in Figure 4). Consequently, the effects of treatments on the performance of BAC HD and YAC128 lines in these tests need to be considered in the context of their effects on body weight.…”

“…HD models in which the full-length HTT transgene is carried in either a yeast or a bacterial artificial chromosome (YAC and BAC, respectively) are also available (Hodgson et al, 1999;Slow et al, 2003;Gray et al, 2008); see Table 1. Unlike the shorter N-terminal fragment models, these larger transgenic constructs have a tendency to integrate into the genome at a single genomic locus and typically in low copy numbers (i.e., 1-3 transgene copies).…”

“…As a result, HTT mRNA and protein expression levels in YAC-and BAC-derived full-length transgenic models tend to correlate well with the number of transgene copies that are inserted. The well-studied YAC128 transgenic mouse, for example, expresses multiple copies of full-length human HTT with 100 and 126 glutamine repeats, encoded by a tract that is composed primarily of CAG codons but also contains 9 interspersed CAA codons (that also encode glutamine) (Pouladi et al, 2012), at roughly the same level (~75%) as the endogenous mouse Htt (Slow et al, 2003). In contrast, the BAC HD mouse model, which expresses full-length human HTT containing 97 codons of a mixed CAG/CAA repeat tract, expresses human HTT at levels 1.5 to 2 times higher than the endogenous mouse Htt (Gray et al, 2008), a function of higher numbers of transgene copies inserted.…”

“…Germ line and somatic instability is not seen over generational time in BAC HD mice. In contrast, the N-terminal HTT fragment transgenic models described above, whose tracts are comprised of (CAG) nCAACAG sequence, exhibit both germ line and somatic instability in individual mice and over generational time (Menalled et al, 2009a;Slow et al, 2003). The DNA sequence encoding the polyglutamine tract has two important implications that should be considered when using the BAC HD and YAC128 mice in HD research.…”

“…The DNA sequence encoding the polyglutamine tract has two important implications that should be considered when using the BAC HD and YAC128 mice in HD research. First, routine measurement of CAG-CAA tract size in each BAC HD and YAC128 animal used for breeding and/ or experimentation is not necessary as the tract sizes are highly stable in the germ line (Gray et al, 2008;Slow et al, 2003). Second, while this stability is convenient in terms of maintaining and breeding these mice for experimentation, questions remain regarding the result of such CAG-CAA sequences on HD pathophysiology in the mouse, especially in the context of the potential role of RNA structure and toxicity (Banez-Coronel et al, 2012) and the importance of somatic instability (Kennedy and Shelbourne, 2000;Swami et al, 2009) in eliciting such pathophysiology.…”