Molecular mechanisms of localised Myelin Basic Protein synthesis in oligodendrocytes

神经元轴突的髓鞘形成和由此产生的动作电位的跳跃性传导是中枢神经系统有效信息处理的先决条件。髓鞘的损伤或缺乏对神经系统功能有戏剧性的影响，多发性硬化症(MS)就是一个例子，这是年轻人最常见的神经系统疾病之一。少突胶质细胞通过合成大量的膜表面积来产生髓鞘，它们包裹在轴突节段并致密。髓鞘碱性蛋白(MBP)是髓鞘的重要组成部分，缺乏它会导致髓鞘不能形成功能性髓鞘。MBP mRNA以RNA颗粒的形式从细胞核转运到细胞膜，在那里根据轴突信号进行局部翻译，从而在时间和空间上调节MBP和最终髓鞘的合成。我们最近发现了一些分子，它们可以刺激MBP mRNA的翻译以响应轴突信号，也可以在运输过程中抑制MBP mRNA的翻译。我们可以证明一种抑制性小RNA分子(NcRNA715)在MS病变中丰富，这可以解释为什么这些病变中的少突胶质细胞不能产生MBP蛋白和髓鞘。在拟议的项目中，我们打算更详细地了解控制MBP翻译从抑制到启动的分子机制。支持的实验将揭示MBP mRNA如何在其细胞目的地从翻译不活跃状态转变为翻译活跃状态。我们打算研究RNA在这方面的潜在作用，并确定控制MBP局部合成的新分子(蛋白质和RNA)。这些研究对于了解MBP-和髓鞘合成是如何调控的很重要，这些基础知识将有助于开发新的脱髓鞘疾病治疗方法，如女士，此外，它们还将有助于更好地理解细胞RNA生物学。

The myelination of neuronal axons and resulting saltatory conduction of action potentials is a prerequisite for efficient information processing in the central nervous system. The damage or lack of myelin has dramatic implications for nervous system function which is exemplified by the disease multiple sclerosis (MS), one of the most common neurologic disorders of young adults. Oligodendrocytes produce myelin by synthesizing huge amounts of membrane surface area which they wrap around axonal segments and compact. Myelin Basic Protein (MBP) is an essential component of myelin and its absence results in an inability to form functional myelin. MBP mRNA is transported in RNA granules from the nucleus to the cell membrane where it is translated locally in response to axonal signals so that MBP and eventually myelin synthesis can be regulated in a temporal and spatial manner. We recently identified molecules which can stimulate MBP mRNA translation in response to axonal signals and which can repress MBP mRNA translation during transport. We could show that an inhibitory small RNA molecule (sncRNA715) is enriched in MS lesions which could explain why oligodendrocytes in these lesions fail to produce MBP protein and myelin. In the proposed projects we intend to obtain a more detailed insight into the molecular mechanisms controlling the transition from inhibition to initiation of MBP translation. The supported experiments will reveal how MBP mRNA is converted from a translationally inactive into a translationally active state at its cellular destination. We intend to investigate a potential role of the RNA modulating Argonaute proteins in this context and to identify new molecules (proteins and RNAs) controlling the localised synthesis of MBP. These studies are important to understand how MBP- and myelin synthesis is regulated and this basic knowledge will contribute to the development of novel therapeutic approaches for demyelinating diseases such as MS. Furthermore they will contribute towards a better understanding of cellular RNA biology.