CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease.
CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington's disease.
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DOI：
10.1093/brain/awv384
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Betuing S
中科院分区：
文献类型：
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作者：
Boussicault L;Alves S;Lamazière A;Planques A;Heck N;Moumné L;Despres G;Bolte S;Hu A;Pagès C;Galvan L;Piguet F;Aubourg P;Cartier N;Caboche J;Betuing S
胆固醇合成失调与亨廷顿病有关。Boussicault等人表明，在患者和小鼠模型中，胆固醇降解的限速酶CYP 46 A1的表达降低。CYP 46 A1的恢复重建了正常的胆固醇水平，具有神经保护作用，这表明靶向胆固醇降解可能具有治疗潜力。 胆固醇合成失调与亨廷顿病有关。Boussicault等人表明，在患者和小鼠模型中，胆固醇降解的限速酶CYP 46 A1的表达降低。CYP 46 A1的恢复重建了正常的胆固醇水平，具有神经保护作用，这表明靶向胆固醇降解可能具有治疗潜力。 亨廷顿病是一种常染色体显性遗传的神经退行性疾病，由亨廷顿蛋白（Exp-HTT）中的异常多聚谷氨酰胺扩增导致纹状体神经元变性引起。脑胆固醇稳态改变与亨廷顿病有关，纹状体神经元中胆固醇积累增加，但胆固醇代谢前体水平降低。为了阐明这两个看似对立的失调，我们研究了胆固醇24-羟化酶（CYP 46 A1）的表达，CYP 46 A1是胆固醇转化为24 S-羟基胆固醇（24 S-OHC）的神经元特异性和限速酶。与对照组相比，死后亨廷顿病患者的壳核中CYP 46 A1蛋白水平降低，但大脑皮质样本中没有。CYP 46 A1 mRNA和CYP 46 A1蛋白水平在R6/2亨廷顿病小鼠模型和ST hdh Q111细胞系的纹状体中也降低。在体内，在野生型环境中，敲低纹状体中的CYP 46 A1表达，通过腺相关病毒介导的选择性shCYP 46 A1的递送，再现了亨廷顿病表型，如通过旋转棒评估的自发性纹状体神经元变性和运动缺陷。在体外，CYP 46 A1恢复保护培养物中表达ST hdh Q111和Exp-HTT的纹状体神经元免于细胞死亡。在R6/2亨廷顿氏病小鼠模型中，腺相关病毒介导的CYP 46 A1向纹状体的递送减少了神经元萎缩，减少了Exp-HTT聚集体的数量、强度水平和大小，并改善了运动缺陷，如通过旋转棒和紧握行为测试所评估的。R6/2小鼠中的腺相关病毒-CYP 46 A1感染也恢复了胆固醇和羊毛甾醇的水平，并增加了链甾醇的水平。在体外，发现羊毛甾醇和链甾醇保护表达Exp-HTT的纹状体神经元免于死亡。我们的结论是，恢复CYP 46 A1在纹状体的活性有望在亨廷顿病的新的治疗方法。
Dysregulation of cholesterol synthesis is implicated in Huntington’s disease. Boussicault et al. show that expression of CYP46A1, the rate-limiting enzyme in cholesterol degradation, is reduced in patients and a mouse model. Restoration of CYP46A1 re-establishes normal cholesterol levels and is neuroprotective, suggesting that targeting cholesterol degradation may have therapeutic potential. Dysregulation of cholesterol synthesis is implicated in Huntington’s disease. Boussicault et al. show that expression of CYP46A1, the rate-limiting enzyme in cholesterol degradation, is reduced in patients and a mouse model. Restoration of CYP46A1 re-establishes normal cholesterol levels and is neuroprotective, suggesting that targeting cholesterol degradation may have therapeutic potential. 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 ST hdh Q111 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 ST hdh Q111 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.