Pikuleva Irina A, Cartier Nathalie
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, United States.
NeuroGenCell, Paris Brain Institute, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France.
Front Aging Neurosci. 2021 Jul 8;13:696778. doi: 10.3389/fnagi.2021.696778. eCollection 2021.
Cholesterol, an essential component of the brain, and its local metabolism are involved in many neurodegenerative diseases. The blood-brain barrier is impermeable to cholesterol; hence, cholesterol homeostasis in the central nervous system represents a balance between biosynthesis and elimination. Cytochrome P450 46A1 (CYP46A1), a central nervous system-specific enzyme, converts cholesterol to 24-hydroxycholesterol, which can freely cross the blood-brain barrier and be degraded in the liver. By the dual action of initiating cholesterol efflux and activating the cholesterol synthesis pathway, CYP46A1 is the key enzyme that ensures brain cholesterol turnover. In humans and mouse models, CYP46A1 activity is altered in Alzheimer's and Huntington's diseases, spinocerebellar ataxias, glioblastoma, and autism spectrum disorders. In mouse models, modulations of CYP46A1 activity mitigate the manifestations of Alzheimer's, Huntington's, Nieman-Pick type C, and Machao-Joseph (spinocerebellar ataxia type 3) diseases as well as amyotrophic lateral sclerosis, epilepsy, glioblastoma, and prion infection. Animal studies revealed that the CYP46A1 activity effects are not limited to cholesterol maintenance but also involve critical cellular pathways, like gene transcription, endocytosis, misfolded protein clearance, vesicular transport, and synaptic transmission. How CYP46A1 can exert central control of such essential brain functions is a pressing question under investigation. The potential therapeutic role of CYP46A1, demonstrated in numerous models of brain disorders, is currently being evaluated in early clinical trials. This review summarizes the past 70 years of research that has led to the identification of CYP46A1 and brain cholesterol homeostasis as powerful therapeutic targets for severe pathologies of the CNS.
胆固醇作为大脑的重要组成部分，其局部代谢参与了多种神经退行性疾病。血脑屏障对胆固醇具有不可渗透性；因此，中枢神经系统中的胆固醇稳态代表了生物合成与清除之间的平衡。细胞色素P450 46A1（CYP46A1）是一种中枢神经系统特异性酶，可将胆固醇转化为24-羟基胆固醇，后者能够自由穿过血脑屏障并在肝脏中降解。通过启动胆固醇外流和激活胆固醇合成途径的双重作用，CYP46A1是确保脑胆固醇周转的关键酶。在人类和小鼠模型中，CYP46A1活性在阿尔茨海默病、亨廷顿病、脊髓小脑共济失调、胶质母细胞瘤和自闭症谱系障碍中发生改变。在小鼠模型中，调节CYP46A1活性可减轻阿尔茨海默病、亨廷顿病、尼曼-匹克C型病和马查多-约瑟夫病（脊髓小脑共济失调3型）以及肌萎缩侧索硬化症、癫痫、胶质母细胞瘤和朊病毒感染的表现。动物研究表明，CYP46A1活性的影响不仅限于胆固醇维持，还涉及关键的细胞途径，如基因转录、内吞作用、错误折叠蛋白清除、囊泡运输和突触传递。CYP46A1如何对这些重要的脑功能发挥中枢控制作用是一个亟待研究的紧迫问题。CYP46A1在众多脑疾病模型中显示出的潜在治疗作用，目前正在早期临床试验中进行评估。本综述总结了过去70年的研究，这些研究已将CYP46A1和脑胆固醇稳态确定为中枢神经系统严重疾病的有力治疗靶点。
