CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease - Microorganismes, Molécules Bioactives et Physiopathologie Intestinale Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2016

CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease

Nicolas Heck
Susanne Bolte

Résumé

Huntington’s disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington’s disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington’s disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington’s disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington’s disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington’s disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington’s disease.
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Dates et versions

hal-01299208 , version 1 (07-04-2016)

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Paternité - Pas d'utilisation commerciale

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Citer

Lydie Boussicault, Sandro Alves, Antonin Lamazière, Anabelle Planques, Nicolas Heck, et al.. CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease. Brain - A Journal of Neurology , 2016, 139 (3), pp.953-970. ⟨10.1093/brain/awv384⟩. ⟨hal-01299208⟩
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