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The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington\u2019s disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin\u2019s gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington\u2019s disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington\u2019s disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington\u2019s disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington\u2019s disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awz174","type":"journal-article","created":{"date-parts":[[2019,6,3]],"date-time":"2019-06-03T19:11:03Z","timestamp":1559589063000},"page":"2432-2450","source":"Crossref","is-referenced-by-count":119,"title":["CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington\u2019s disease"],"prefix":"10.1093","volume":"142","author":[{"given":"Radhia","family":"Kacher","sequence":"first","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine, CNRS UMR 8246\/INSERM U1130., Sorbonne Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonin","family":"Lamazi\u00e8re","sequence":"additional","affiliation":[{"name":"LBM, CNRS UMR7203\/INSERM U1157, Sorbonne Universit\u00e9, Facult\u00e9 de M\u00e9decine, AP-HP, H\u00f4pital Saint Antoine, D\u00e9partement PM2, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Heck","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine, CNRS UMR 8246\/INSERM U1130., Sorbonne Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Kappes","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine, CNRS UMR 8246\/INSERM U1130., Sorbonne Universit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coline","family":"Mounier","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine, CNRS UMR 8246\/INSERM U1130., Sorbonne Universit\u00e9, Paris, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilhelm","family":"Christaller","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, Grenoble Institut des Neurosciences, INSERM U1216, CHU Grenoble Alpes, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Sasidharan Nair","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique, Research Unit Biology of Adaptation and Aging (B2A), Team Compensation in Neurodegenerative and Aging (Brain-C), F-75252, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Messent","sequence":"additional","affiliation":[{"name":"Neuroplasticity of Reproductive Behaviors, Sorbonne Universit\u00e9, CNRS, INSERM, Neurosciences Paris Seine, Institut de Biologie Paris Seine, Facult\u00e9 des Sciences et Ing\u00e9nierie, INSERM\/UMR-S 1130, CNRS\/UMR 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