Investigating deficits of axonal RNA metabolism and axonal signalling in amyotrophic lateral sclerosis

肌萎缩侧索硬化症(ALS)，又称运动神经元病(MND)，是一种破坏性的神经退行性疾病，可导致肌肉功能进行性丧失和瘫痪。肌萎缩侧索硬化症是无法治愈的，并会导致死亡，通常是由呼吸困难引起的，平均在确诊后3年内，一生中有大约1/400的风险。在这种疾病中受影响的主要细胞是称为运动神经元(MNS)的神经细胞，它们在ALS过程中逐渐死亡。MN是身体中最大的细胞之一，它将大脑和脊髓与肌肉连接起来，从而使运动成为可能。为了做到这一点，MNS依靠一个名为轴突的细小突起，它从脊髓延伸到我们身体的每一块肌肉。在成年人中，一个轴突可以超过一米长，从脊髓延伸到我们的手指或脚趾，需要复杂的运输和通讯系统才能生存和发挥作用。重要的是，研究表明，在ALS和其他不治之症的早期阶段，轴突的异常就会被发现。一个人体内的所有细胞虽然彼此非常不同，但含有相同的遗传物质，称为DNA，它向每个单独的细胞发出指令。因此，每种细胞类型(例如，MN或心脏细胞)的特性是DNA的哪些部分活跃并产生另一种称为RNA的化学物质的结果。RNA携带细胞运作所需的所有信息。一个细胞中所有RNA的总和，称为转录组，是每种细胞类型的特征。了解某种细胞类型的转录组有助于深入了解其生物学特性，并有助于确定疾病的原因。这与肌萎缩侧索硬化症的MNS尤其相关，因为有良好的证据表明，与RNA代谢相关的生物过程主要在ALS中受到影响。此外，RNA在轴突中运输，这对轴突的维持及其对损伤的反应是必不可少的。上面总结的发现强调了：1)轴突参与了疾病的早期阶段；2)ALS是由MNS中RNA谱系的变化引起的，加上来自我赞助商实验室的新的初步数据，这些数据表明3)关键的ALS分子定位于参与轴突通信系统的细胞器，所有这些都聚集在一起形成了我的研究问题。我将使用一个新的ALS动物模型来研究：a)轴突的RNA发生了哪些变化；b)这些变化如何在ALS中发挥作用；c)轴突和细胞体之间的通信系统在ALS中是如何受到影响的。由我的赞助商的实验室和合作者提供的最新技术进步确保了这个项目的可行性。这些尖端的方法将使我能够分离和研究在MN及其轴突中专门发现的RNA。此外，我将能够分离出有助于在MN轴突中传递生存信号的小颗粒。总而言之，这个项目将有助于了解轴突是如何正常运作的，以及ALS中哪里出了问题。这将极大地帮助我们了解ALS的发病机制，并发现有效治疗ALS的新靶点。

Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease (MND), is a devastating neurodegenerative disorder which causes progressive loss of muscle function and paralysis. ALS is incurable and leads to death, usually caused by the inability to breathe, on average only 3 years after diagnosis, with a lifetime risk of about 1 in 400. The main cells affected in this disease are nerve cells called motor neurons (MNs), which progressively die during the course of ALS. MNs are amongst the largest cells of the body and connect the brain and the spinal cord to the muscles therefore making movement possible. In order to do this, MNs rely on one thin process, named the axon, which extends from the spinal cord out to each and every muscle of our body. In adults, a single axon can measure over a meter, running from the spinal cord to our fingers or toes, and needs sophisticated transport and communication systems to survive and function. Importantly, research has shown that abnormalities in axons are found in the very early stages of ALS and other incurable human diseases. All cells in an individual's body, although very diverse from each other, contain the same genetic material called DNA, that gives instructions to each individual cell. Therefore the identity of each cell type (whether a MN or a heart cell, for example) is the result of which portions of DNA are active and produce another type of chemical called RNA. RNA carries all the necessary information for the cell to function. The sum of all the RNA in a cell, named the transcriptome, is the signature that characterises each cell type. Knowing the transcriptome of a certain cell type provides insights into its biology and helps determine the causes of diseases. This is particularly relevant with MNs in ALS since there is good evidence showing that the biological processes linked to RNA 'metabolism' are primarily affected in ALS.Further, RNA is transported in axons and this is essential for axon maintenance and its response to injuries. The findings summarized above, highlighting that: 1) axons are involved in early stages of disease; and 2) ALS is caused by alterations of the RNA repertoire in MNs, alongside with novel preliminary data from my Sponsor's laboratory which shows that 3) key ALS molecules localise to cellular organelles which are involved in the communication system of axons, all converge to form my research questions.I will use a novel animal model of ALS to investigate: a) Which changes occur in the RNA of axons; b) How these changes can play a role in ALS; c) How the communication system between axons and the cell body is affected in ALS. The feasibility of this project is ensured by the recent technological advances provided by my Sponsor's laboratory and collaborators. These cutting edge approaches will allow me to isolate and study RNA specifically found in MNs and their axons. Further, I will be able to isolate the small particles that contribute to transmitting survival signals in MN axons. In summary this project will contribute to understand how axons function normally and what goes wrong in ALS. This will greatly help us to understand disease mechanisms and discover novel targets for effective therapies for ALS.