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

摘要: Aims: Huntington 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, distribution and timing of HTT-lowering therapies required for beneficial effect less clear. Here, we investigated whether HD-related behaviours could be prevented by inactivating mutant HTT at stages varying degrees an experimental model. Methods: We generated BACHD mice either widespread or circuit-specific inactivation Cre recombinase (Cre) under nestin promoter adenosine A2A receptor respectively. also simulated gene therapy scenario allele-specific targeting injections recombinant adeno-associated viral (rAAV) vectors expressing into striatum adult mice. All were assessed behavioural tests investigate motor, metabolic psychiatric outcome measures 4–6 months age. Results: While motor deficits, body weight changes, anxiety depressive-like present mice, early CNS during development significantly improves rotarod performance, changes behaviour. However, conditional circuit-wide deletion from indirect striatal pathway focal striatal-specific adulthood failed rescue any behaviours. Conclusions: Our results indicate that interventions aimed reducing important factors consider when developing HD. (Less)