Recent findings emphasise impairment of cholesterol homeostasis in HD pathogenesis. Cellular cholesterol synthesis and metabolism in HD patients and animal models are altered. Blood concentration of the brain cholesterol metabolite, 24S-hydroxycholesterol, is decreased in HD patients. Moreover, cholesterol membrane accumulation has been shown in cellular and mouse model of HD. We postulated that CYP46A1, the enzyme responsible for the conversion of cholesterol into 24S-hydroxycholesterol, could account for altered cholesterol content and neuropathology in HD. We first showed that cyp46A1mRNA levels are decreased within the striatum of the R6/2 mouse model at early stages as well as in STHdh Q111 cell line. Interestingly, CYP46A1 protein expression is also significantly decreased in HD patient putamen extracts. Furthermore, restoring CYP46A1 expression in vitrowas neuroprotective in a model system of primary striatal neurons that expressed polyQ-HTT. We then restored CYP46A1 expression in the striatum of R6/2 HD mouse models, using AAVrh10 vector. After AAV10rh-CYP46A1 stereotaxic injection in the striatum, we showed a widespread expression of the transgene with a particular tropism for neuronal cells. When compared to control groups, R6/2 mice injected with AAV10rh-CYP46A1 exhibited lower clasping score as well as improvement of rotarod performance over time. Neuroprotection was observed in post-mortem striatal sections with a delay of aggregate formation, restoration of MSK-1 transcript levels and increased striatal nucleus area as well as a rescue of cholesterol metabolism quantified with mass sprectrometry. Overall this study provides a body of preclinical informations to propose a new target with potential efficacy in HD patients based on CYP46A1 restoration.
- cholesterol metabolism
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