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传导是中枢神经系统中有效信息处理的先决条件。髓磷脂的损伤或缺乏对神经系统功能具有戏剧性的影响，这由多发性硬化症（MS）疾病（年轻成年人最常见的神经系统疾病之一）例示。少突胶质细胞通过合成大量的膜表面积来产生髓鞘，它们包裹轴突节段并压实。髓鞘碱性蛋白（MBP）是髓鞘的重要组成部分，它的缺乏导致不能形成功能性髓鞘。MBP mRNA在RNA颗粒中从细胞核转运到细胞膜，在细胞膜中它响应于轴突信号而局部翻译，使得MBP和最终髓鞘合成可以以时间和空间方式调节。最近，我们确定了分子，可以刺激MBP mRNA的翻译响应轴突信号，并可以抑制MBP mRNA的翻译在运输过程中。我们可以证明，抑制性小RNA分子（sncRNA715）在MS病变中富集，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，我们打算获得一个更详细的深入了解的分子机制控制从抑制到启动MBP翻译的过渡。支持的实验将揭示MBP mRNA如何在其细胞目的地从非激活的非激活状态转化为激活状态。我们打算研究RNA调节Argonaute蛋白在这种情况下的潜在作用，并鉴定控制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节的非常重要，这些基础知识将有助于开发脱髓鞘疾病（如MS）的新治疗方法。此外，它们将有助于更好地了解细胞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.