Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington's disease

Neuronal intranuclear inclusions are a histopathological hallmark of Huntin gton's disease. Nevertheless, the precise mechanism by which they are forme d and their relevance to neuronal cell death and/or dysfunction remains unc lear. We recently generated a conditional mouse model of Huntington's disea se (HD94) in which silencing expression of mutated huntingtin led to the di sappearance of intranuclear aggregates and amelioration of the behavioral p henotype. Here, we analyze primary striatal neuronal cultures from HD94 mic e to explore the dynamics of aggregate formation and reversal, the possible mechanisms involved, and the correlation between aggregates and neuronal d eath. In parallel, we examine symptomatic adult HD94 mice in similar studie s and explored the relationship between aggregate clearance and behavioral reversal. We report that, in culture, aggregate formation and reversal were rapid processes, such that 2 d of transgene expression led to aggregate fo rmation, and 5 d of transgene suppression led to aggregate disappearance. I n mice, full reversal of aggregates and intranuclear mutant huntingtin was more rapid than reported previously and preceded the motor recovery by seve ral weeks. Furthermore, the proteasome inhibitor lactacystin inhibited the aggregate clearance observed in culture, thus indicating that aggregate for mation is a balance between the rate of huntingtin synthesis and its degrad ation by the proteasome. Finally, neither expression of the mutant huntingt in nor aggregates compromised the viability of HD94 cultures. This correlat ed with the lack of cell death in symptomatic HD94 mice, thus demonstrating that neuronal dysfunction, and not cell loss, triggered by mutant huntingt in underlies symptomatology.