Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin protein leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in HD pathogenesis. Indeed, the expressions of several genes involved in cholesterol biosynthetic pathway and cholesterol precursor metabolites are reduced in murine models of HD (Valenza, 2007). For HD-patients, the decrease of plasma 24S-hydroxycholesterol (24 OHC), the product of brain cholesterol clearance, follows disease progression proportionally to motor and neuropsychiatric dysfunction (Leoni, 2013). Data related to striatal cholesterol levels are more conflicting. The team investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion into 24S-OHC. CYP46A1 expression is decreased in putamen human extracts, in the R6/2 transgenic mouse model and HD cell lines. CYP46A1 restoration in cellular model is neuroprotective and in R6/2 mice it alleviates locomotor phenotypes and improves neuropathology as well as sterol metabolism (Boussicault, 2016). To validate and confirm the neuroprotective effect of CYP46A1 in HD, a more progressive HD mouse model has been investigated, the zQ175 Knock-In mice. After striatal injection of an AAVrh10-CYP46A1 at 4 months, motor behaviour was evaluated from 7 to 11 months in WT, heterozygous and homozygous mice. Neuropathological landmarks were assessed using immunochemistry labelling for aggregates, DARPP32 and NeuN. Next, lipidomic study will be performed to follow cholesterol metabolism regulation by CYP46A1. This study will bring new insights about cholesterol metabolism involvement in HD and will assess the potential of CYP46A1 as a new therapeutic target.
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