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CYP46A1 protects against NMDA-mediated excitotoxicity in Huntington's disease: Analysis of lipid raft content
Biochimie ( IF 3.9 ) Pub Date : 2018-08-11 , DOI: 10.1016/j.biochi.2018.07.019
Lydie Boussicault , Radhia Kacher , Antonin Lamazière , Peter Vanhoutte , Jocelyne Caboche , Sandrine Betuing , Marie-Claude Potier

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (mHtt) protein leading to degeneration of striatal neurons. Excitotoxicity, consecutive to overstimulation of N-methyl d-aspartate receptors (NMDARs) has a pivotal role in many neurological disorders including HD. Mutant Htt causes enhanced NMDA sensitivity, alteration of NMDAR expression and localization in neurons. Excitotoxic events initiate neuronal death in numerous ways, including activation of apoptotic cascades. Among the NMDAR subunits involved in glutamatergic-mediated excitotoxicity, GluN2B has been extensively reported. In addition to excitotoxicity, alteration of cholesterol metabolism has been observed in HD, with a decrease of cholesterol precursor synthesis along with an increase of cholesterol accumulation, which is deleterious for neurons. Expression of Cholesterol Hydroxylase enzyme, CYP46A1, which converts cholesterol into 24 S-hydroxycholesterol is down-regulated in HD. We found that CYP46A1 overexpression is beneficial in HD neurons and mouse model, but the mechanisms involved still remain unclear. In this study we addressed the effect of CYP46A1 on NMDAR-mediated excitotoxicity in HD primary neurons and its role in modulating cholesterol and localization of GLUN2B in lipid rafts. We showed that CYP46A1 is protective against NMDAR-mediated excitotoxicity in two different HD neuronal cell models. Cholesterol as well as GluN2B level in lipid raft, are significantly increased by mHtt. Despite a clear effect of CYP46A1 in reducing cholesterol content in lipid raft extracts from wild type neurons, CYP46A1 overexpression in HD neurons could not normalize the increased cholesterol levels in lipid rafts. This study highlights the beneficial role of CYP46A1 against NMDAR-mediated excitotoxicity and gives further insights into the cellular mechanisms underlying CYP46A1-mediated neuroprotection.



中文翻译:

CYP46A1在亨廷顿舞蹈病中预防NMDA介导的兴奋性毒性:脂筏含量分析

亨廷顿舞蹈病(HD)是一种常染色体显性遗传神经退行性疾病,由亨廷顿蛋白(mHtt)中异常的多聚谷氨酰胺膨胀引起,导致纹状体神经元变性。兴奋性毒性,连续刺激N-甲基d天门冬氨酸受体(NMDARs)在包括HD在内的许多神经系统疾病中具有关键作用。突变的Htt导致NMDA敏感性增强,NMDAR表达改变和神经元定位。兴奋性毒性事件以多种方式引发神经元死亡,包括激活凋亡级联反应。在涉及谷氨酸能介导的兴奋性毒性的NMDAR亚基中,已广泛报道了GluN2B。除了兴奋性毒性外,HD中还观察到胆固醇代谢的改变,胆固醇前体合成减少,胆固醇积累增加,这对神经元有害。将胆固醇转化为24 S-羟基胆固醇的胆固醇羟化酶CYP46A1的表达在HD下调。我们发现CYP46A1过表达在HD神经元和小鼠模型中是有益的,但所涉及的机制仍不清楚。在这项研究中,我们研究了CYP46A1对HD原代神经元中NMDAR介导的兴奋性毒性的作用及其在调节胆固醇和脂质筏中GLUN2B定位中的作用。我们显示CYP46A1在两种不同的HD神经元细胞模型中对NMDAR介导的兴奋性毒性具有保护作用。mHtt可显着增加脂质筏中的胆固醇以及GluN2B水平。尽管CYP46A1明显降低了野生型神经元脂质筏提取物中的胆固醇含量,但CYP46A1在高清神经元中的过表达不能使脂质筏中升高的胆固醇水平正常化。

更新日期:2018-08-11
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