UNIVERSITY OF FLORIDA
See comment.This project uses recombinant adeno-associated viral vectors to deliver genes encoding constructs to knock-down huntingtin in striatal neurons. Long-term knock-down of striatal huntingtin will test the hypothesis that reduced huntingtin expression should limit the formation of neuronal Intranuclear inclusions in transduced neurons and thereby slow disease progression in mouse models of HD. We will use small interfering RNAs (siRNAs) to knock-down huntingtin in striatal neurons. Moreover, we propose two ways to test the hypothesis that normal huntingtin expression is beneficial.. First, we will compare the effects of huntingtin knock-down in both knock-in HD mice and transgenic HD mice. Since transgenic HD mice still express the normal amount of mouse huntingtin, our hypothesis predicts that huntingtin knock-down will be more beneficial in the transgenic mice compared to the knock-in HD mice that have only mutant huntingtin expression. Second, it is unclear whether striatal dysfunction originates in a cell autonomous fashion in striatal neurons or is caused by mutant huntingtin-induced cortico-striatal dysfunction. We will directly test this hypothesis by transducing cortical areas vs. striatal areas. We will use reduction in the amount of striatal neuronal nuclear inclusions and reversal of known transcriptional changes as our initial screen for beneficial effects followed by detailed functional analysis of motor behavior as metric of success of these strategies.