Background The amelioration of behavioural and neuropathological deficits in mice expressing caspase 6 resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine track, highlights proteolysis of htt at the 586aa caspase 6 (casp6) site as a key mechanism in the pathology of HD. In order to determine whether C6R mhtt acts as a dominant negative inhibitor of casp6 activation, we crossed C6R mice to the YAC128 HD mouse model. If the neuroprotection observed in C6R mice reflects a dominant negative effect, then similar protection and amelioration of HD related phenotypes may be expected in mice expressing both casp6 cleavable and casp6 resistant mhtt.

Results Neuropathological analysis of YAC128/C6R brains reveals a significant decrease in brain weight (p<0.01) and striatal volume (p<0.01) in the YAC128/C6R mice, similar to what is observed in the YAC128 mice (brain weight p<0.05; striatal volume p<0.05). In contrast, and similar to previous findings, C6R brains demonstrated preserved brain weight and striatal volume. Furthermore, the 586aa mhtt fragment is observed in YAC128/C6R brain tissue. Behavioural testing reveals that the YAC128/C6R mice perform similar to YAC128 mice in the open field. Body weight in significantly increased in the YAC128/C6R mice compared with YAC128 due to the increased levels of htt in these mice.

Conclusion These data suggest that the lack of an HD phenotype in the C6R mice is due to the absence of the 586aa mhtt fragment and provide additional evidence that the 586aa mhtt fragment plays a critical role in the pathogenesis of HD. This work supports efforts towards casp6 inhibition as a therapeutic treatment for HD.