Effects of mutant huntingtin inactivation on Huntington disease-related behaviours in the BACHD mouse model.

aimsHuntington disease (HD) is a fatal neurodegenerative disorder with no disease-modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT-lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD-related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model.

methodsWe generated mutant BACHD mice with either a widespread or circuit-specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A

resultsWhile motor deficits, body weight changes, anxiety and depressive-like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive-like behaviour. However, conditional circuit-wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal-specific deletion in adulthood failed to rescue any of the HD-related behaviours.

conclusionsOur results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease-modifying therapies for HD.