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• W2964710007 endingPage "2450" @default.
• W2964710007 startingPage "2432" @default.
• W2964710007 abstract "Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. 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's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's 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's 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's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's 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's 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's disease." @default.
• W2964710007 created "2019-08-13" @default.
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• W2964710007 date "2019-07-09" @default.
• W2964710007 modified "2023-10-18" @default.
• W2964710007 title "CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease" @default.
• W2964710007 cites W1550784771 @default.
• W2964710007 cites W1564028006 @default.
• W2964710007 cites W1567203515 @default.
• W2964710007 cites W1824457652 @default.
• W2964710007 cites W1963021413 @default.
• W2964710007 cites W1964215406 @default.
• W2964710007 cites W1965530119 @default.
• W2964710007 cites W1966066277 @default.
• W2964710007 cites W1977767269 @default.
• W2964710007 cites W1982493902 @default.
• W2964710007 cites W1984394485 @default.
• W2964710007 cites W1992465104 @default.
• W2964710007 cites W1993629125 @default.
• W2964710007 cites W1994447059 @default.
• W2964710007 cites W2008823657 @default.
• W2964710007 cites W2009959558 @default.
• W2964710007 cites W2010404670 @default.
• W2964710007 cites W2011513402 @default.
• W2964710007 cites W2016742032 @default.
• W2964710007 cites W2018088211 @default.
• W2964710007 cites W2022791592 @default.
• W2964710007 cites W2023868477 @default.
• W2964710007 cites W2025836185 @default.
• W2964710007 cites W2025872849 @default.
• W2964710007 cites W2029177106 @default.
• W2964710007 cites W2033082596 @default.
• W2964710007 cites W2038083025 @default.
• W2964710007 cites W2039077622 @default.
• W2964710007 cites W2039999119 @default.
• W2964710007 cites W2040671431 @default.
• W2964710007 cites W2044654185 @default.
• W2964710007 cites W2046045564 @default.
• W2964710007 cites W2048323087 @default.
• W2964710007 cites W2049528479 @default.
• W2964710007 cites W2051897382 @default.
• W2964710007 cites W2052496080 @default.
• W2964710007 cites W2061354173 @default.
• W2964710007 cites W2071533902 @default.
• W2964710007 cites W2073466689 @default.
• W2964710007 cites W2074400763 @default.
• W2964710007 cites W2074561520 @default.
• W2964710007 cites W2081722421 @default.
• W2964710007 cites W2085838487 @default.
• W2964710007 cites W2094749019 @default.
• W2964710007 cites W2095099413 @default.
• W2964710007 cites W2099685145 @default.
• W2964710007 cites W2109554433 @default.
• W2964710007 cites W2113263629 @default.
• W2964710007 cites W2114806174 @default.
• W2964710007 cites W2116449089 @default.
• W2964710007 cites W2121642311 @default.
• W2964710007 cites W2121760835 @default.
• W2964710007 cites W2128775004 @default.
• W2964710007 cites W2129447571 @default.
• W2964710007 cites W2131766165 @default.
• W2964710007 cites W2133229132 @default.
• W2964710007 cites W2135007868 @default.
• W2964710007 cites W2136140769 @default.
• W2964710007 cites W2139947061 @default.
• W2964710007 cites W2140795771 @default.
• W2964710007 cites W2140869639 @default.
• W2964710007 cites W2143827549 @default.
• W2964710007 cites W2146124002 @default.
• W2964710007 cites W2147413218 @default.
• W2964710007 cites W2148659064 @default.
• W2964710007 cites W2155858151 @default.
• W2964710007 cites W2156621978 @default.
• W2964710007 cites W2160394687 @default.
• W2964710007 cites W2162014027 @default.
• W2964710007 cites W2171705910 @default.
• W2964710007 cites W2267942984 @default.
• W2964710007 cites W2274495055 @default.
• W2964710007 cites W2279325731 @default.
• W2964710007 cites W2482259472 @default.
• W2964710007 cites W2504409177 @default.

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