Recently, altered brain cholesterol homeostasis has been implicated in Huntington’s disease (HD) pathogenesis. Our team made the original observation that expression level of CYP46A1, the rate-limiting enzyme for the degradation of cholesterol in the brain, is decreased in putamen extracts of post-mortem HD patients and in the striatum of an HD knock-in (KI) mouse model, the zQ175 mice.Method
We restored CYP46A1 expression into the striatum of zQ175 mice, at a pre-symptomatic stage, using an AAV-mediated approach. A battery of behavioral, neuropathological and molecular tests was performed in these mice.Results
In zQ175 mice injected with CYP46A1, locomotor activity and histological landmarks were improved; aggregates number and size were decreased and striatal projection neurons soma size was increased. In these mice, cholesterol homeostasis is restored with not only an increase of cholesterol degradation but also a regulation of cholesterol synthesis, with increased cholesterol precursor’s levels, thus a regulation of the whole pathway. Complementary studies showed that CYP46A1 improves the synaptic connectivity and the glutamatergic transmission in the striatum of zQ175 mice. Additionally, we showed that CYP46A1 increases BDNF vesicle axonal transport as well as TrkB receptor endosome trafficking in HD cortico-striatal connections reconstituted in microfluidic devices. Finally, we report that CYP46A1-regulated sterols, lanosterol and desmosterol, increased the clearance of mHTT aggregates through proteasome and autophagy machineries.Conclusion
In the present project, we showed that CYP46A1 restoration alleviates the pathological phenotype of zQ175 mice. Collectively, our results provide a comprehensive model for the mechanisms by which CYP46A1 striatal restoration may promote brain homeostasis and oppose HD, opening a novel therapeutic avenue based on promoting compensation of HD phenotype.