title: CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease.
abstract: 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.
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Boussicault
authors.affiliation: 2 INSERM U1169, Le Kremlin-Bicêtre, MIRCEN CEA and Université Paris-Sud, Université Paris Saclay, 91400 Orsay, France.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.affiliation: 3 Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités- Université Pierre et Marie Curie-Paris 6, CHU Saint-Antoine, 75012 Paris, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Lamazière
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France 4 Development and Neuropharmacology, Center for Interdisciplinary Research in Biology, INSERM CNRS 7141. Collège de France.
authors.forename: Anabelle
authors.initials: A
authors.lastname: Planques
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Heck
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France.
authors.forename: Lara
authors.initials: L
authors.lastname: Moumné
authors.affiliation: 3 Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités- Université Pierre et Marie Curie-Paris 6, CHU Saint-Antoine, 75012 Paris, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Despres
authors.affiliation: 5 Cellular Imaging Facility, Institute of Biology Paris-Seine CNRS FR, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bolte
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France 6 Laboratory of Experimental Neurology, Université Libre de Bruxelles, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Hu
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pagès
authors.affiliation: 7 Semel Institute, University California Los Angeles, Los Angeles, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Galvan
authors.affiliation: 8 Department of Translational Medicine and Neurogenetics, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), UMR 7104 CNRS/UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Piguet
authors.affiliation: 2 INSERM U1169, Le Kremlin-Bicêtre, MIRCEN CEA and Université Paris-Sud, Université Paris Saclay, 91400 Orsay, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: 2 INSERM U1169, Le Kremlin-Bicêtre, MIRCEN CEA and Université Paris-Sud, Université Paris Saclay, 91400 Orsay, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France jocelyne.caboche@upmc.fr sandrine.betuing@upmc.fr.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caboche
authors.affiliation: 1 Neuronal Signaling and Gene Regulation, Neurosciences Paris Seine, Institute of Biology Paris-Seine, Sorbonne Universités, UPMC Université Pierre et Marie Curie-Paris 6, INSERM/UMR-S 1130, CNRS/UMR 8246, 75005 Paris, France jocelyne.caboche@upmc.fr sandrine.betuing@upmc.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Betuing
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008875:Middle Aged; D013250:Steroid Hydroxylases / Q000096:biosynthesis*
chemical_list: D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase
keywords: CYP46A1; Huntington’s disease; cholesterol; neuroprotection; striatum