Moutinho Miguel, Nunes Maria João, Rodrigues Elsa
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Exp Cell Res. 2017 Nov 1;360(1):55-60. doi: 10.1016/j.yexcr.2017.02.034. Epub 2017 Feb 21.
Cholesterol homeostasis greatly impacts neuronal function due to the essential role of this sterol in the brain. The mevalonate (MVA) pathway leads to the synthesis of cholesterol, but also supplies cells with many other intermediary molecules crucial for neuronal function. Compelling evidence point to a model in which neurons shutdown cholesterol synthesis, and rely on a shuttle derived from astrocytes to meet their cholesterol needs. Nevertheless, several reports suggest that neurons maintain the MVA pathway active, even with sustained cholesterol supply by astrocytes. Hence, in this review we focus not on cholesterol production, but rather on the role of the MVA pathway in the synthesis of particular intermediaries, namely isoprenoids, and on their role on neuronal function. Isoprenoids act as anchors for membrane association, after being covalently bound to proteins, such as most of the small guanosine triphosphate-binding proteins, which are critical to neuronal cell function. Based on literature, on our own results, and on the analysis of public transcriptomics databases, we raise the idea that in neurons there is a shift of the MVA pathway towards the non-sterol branch, responsible for isoprenoid synthesis, in detriment to post-squalene branch, and that this is ultimately essential for synaptic activity. Nevertheless new tools that facilitate imaging and the biochemical characterization and quantification of the prenylome in neurons and astrocytes are needed to understand the regulation of isoprenoid production and protein prenylation in the brain, and to analyze its differences on diverse physiological or pathological conditions, such as aging and neurodegenerative states.
胆固醇稳态对神经元功能有重大影响，因为这种甾醇在大脑中起着至关重要的作用。甲羟戊酸（MVA）途径不仅导致胆固醇的合成，还为细胞提供许多对神经元功能至关重要的其他中间分子。有力的证据指向一种模型，即神经元关闭胆固醇合成，并依赖源自星形胶质细胞的转运来满足其胆固醇需求。然而，一些报告表明，即使星形胶质细胞持续提供胆固醇，神经元仍保持MVA途径活跃。因此，在本综述中，我们关注的不是胆固醇的产生，而是MVA途径在特定中间体（即类异戊二烯）合成中的作用，以及它们对神经元功能的作用。类异戊二烯在共价结合到蛋白质（如大多数对神经元细胞功能至关重要的小GTP结合蛋白）后，作为膜结合的锚定物。基于文献、我们自己的结果以及对公共转录组学数据库的分析，我们提出这样一种观点，即在神经元中，MVA途径向负责类异戊二烯合成的非甾醇分支转移，不利于角鲨烯后分支，而这最终对突触活动至关重要。然而，需要新的工具来促进对神经元和星形胶质细胞中类异戊二烯组的成像、生化表征和定量，以了解大脑中类异戊二烯产生和蛋白质异戊二烯化的调控，并分析其在不同生理或病理条件（如衰老和神经退行性状态）下的差异。
