Dysfunctions in brain cholesterol homeostasis have been extensively related to 
brain disorders. The main pathway for brain cholesterol elimination is its 
hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, 
CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the 
pathogenesis and progression of neurodegenerative disorders, and that increasing 
its levels in the brain is neuroprotective. However, the mechanisms underlying 
this neuroprotection remain to be fully understood. Huntington's disease is a 
fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG 
expansion in huntingtin's gene. Among the multiple cellular and molecular 
dysfunctions caused by this mutation, altered brain cholesterol homeostasis has 
been described in patients and animal models as a critical event in Huntington's 
disease. Here, we demonstrate that a gene therapy approach based on the delivery 
of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, 
has a long-lasting neuroprotective effect in Huntington's disease and 
counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 
Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and 
restored cholesterol homeostasis. These events were associated to a specific 
striatal transcriptomic signature that compensates for multiple mHTT-induced 
dysfunctions. We thus explored the mechanisms for these compensations and showed 
an improvement of synaptic activity and connectivity along with the stimulation 
of the proteasome and autophagy machineries, which participate to the clearance 
of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal 
transport and TrkB endosome trafficking were restored in a cellular model of 
Huntington's disease. These results highlight the large-scale beneficial effect 
of restoring cholesterol homeostasis in neurodegenerative diseases and give new 
opportunities for developing innovative disease-modifying strategies in 
Huntington's disease.