Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease

YAC18/128 mice were found to express mutant htt at the same level as YAC128 mice and wild-type htt at the same level as YAC18 mice. YAC18/128 mice show no significant behavioural improvement compared to YAC128 mice in the rotarod test of motor coordination or in an automated open field test. In the brain, YAC18/128 mice show no significant improvement in striatal volume, striatal neuronal numbers or striatal DARPP-32 expression compared to YAC128 mice. In contrast, striatal neuronal cross-sectional area showed significant improvement in YAC18/128 mice compared to YAC128 mice.While the over-expression of wild-type htt results in a mild improvement in striatal neuropathology in YAC128 mice, our findings suggest that treatment with wild-type htt may not be sufficient to ameliorate the symptoms of HD in this model.Huntington disease (HD) is an autosomal dominant disorder resulting from a trinucleotide CAG expansion in the HD gene. While the expression of mutant htt is sufficient to cause HD-like symptoms with normal expression levels of wild-type htt [1-3], recent data suggests that decreased levels of wild-type htt in HD patients may also contribute significantly to the pathogenesis of HD [4]. In support of this, we have recently demonstrated that the loss of wild-type htt in YAC128 mice significantly worsens motor performance, survival and striatal neuronal size [5].Htt function is essential for development as mice homozygous for the targeted inactivation of the mouse HD gene are embryonic lethal [6-8]. Furthermore, decreasing htt levels by 50% or more from birth results in neurological abnormalities [7,9,10]. The expression of wild-type htt is also essential postnatally as mice expressing decreased levels of wild-type htt in the forebrain beginning at postnatal day 5 were shown to have a progressive neurological phenotype [11]. Clearly, decreased wild-type htt levels alone can lead to phenotypic abnormalities independent of mutant htt.As the functions of wild-type ht