The role of Miro and PKC signalling in axonal transport defects in amyotrophic lateral sclerosis.

在英国，任何时候都有约6000人患有运动神经元疾病（MND）。MND是一种致命的神经退行性疾病，涉及运动神经元的选择性丧失。运动神经元是将大脑信号传递给肌肉的神经细胞（例如移动手指）。它们有细胞体和连接肌肉的长线状延伸。这些延伸被称为轴突。在精神分裂症中，轴突会断裂，因此大脑和肌肉之间的联系就会消失。这会导致进行性肌肉无力和萎缩，最终导致瘫痪，无法说话或吞咽，最终停止呼吸。利鲁唑目前是英国唯一获准用于治疗精神疾病的药物。虽然利鲁唑可以适度提高生存率，但它不能治愈，也不能修复患者开始服用利鲁唑时已经存在的运动神经元损伤。为了开发更好的MND治疗方法，我们需要更好地了解这种疾病的原因。我们在这里提出的研究是为了找出导致MND运动神经元死亡的事件。我们的研究集中在寻找运动神经元轴突是如何在MND中分解的，因为这是在该疾病的实验室模型中最先看到的东西之一。我们特别关注一个叫做“轴突运输”的过程。大多数轴突构件都是在细胞体中制造的，并且必须被运送到轴突的目的地。这种“输送服务”被称为轴突运输。从技术上讲，轴突运输很像火车旅行：分子马达（“火车头”）与货物（“车厢”）相连，它们在称为微管的蛋白质轨道（“轨道”）上行驶，并燃烧称为ATP的“燃料”来实现这一目标。当轴突运输中断时，轴突就会因为没有供体而挨饿，最终神经死亡。我们发现一种叫做线粒体的特殊货物的轴突运输在MND中是有缺陷的。线粒体对神经非常重要，因为它们产生ATP燃料，为一切提供能量；换句话说，线粒体是细胞的发电站。在MND中，运输系统的破坏导致轴突中线粒体的减少，这很可能导致轴突因缺乏燃料而死亡。我们不知道的是导致这种崩溃的原因。就像火车旅行一样，轴突运输的缺陷可以通过许多途径产生：也许缺少了一个重要的组成部分？是“火车头”（分子马达）受损，还是缺乏“燃料”（ATP）？“车厢”（线粒体）和“火车头”之间的联系断裂了吗？“轨道”（微管）被破坏了吗？或者，是否存在信号故障？我们已经知道，在一种遗传性MND中，信号分子钙的过剩会导致线粒体运输缺陷。在这个项目中，我们想要调查在其他形式的MND中是否也存在这种情况，看看这是否是所有MND共同的缺陷。我们还想研究钙是如何阻止运输的。一旦我们确切地发现这种缺陷是如何引起的，我们将试图阻止这种缺陷或恢复运输，并测量这是否能保护运动神经元免于死亡。总之，这项研究将调查导致MND关键事件的事件，具有未来药物开发的潜力。此外，由于轴突运输缺陷也见于其他神经退行性疾病，包括阿尔茨海默氏病和帕金森病，因此结果可能对这些疾病也有帮助。

In the UK approximately 6,000 people suffer from motor neuron disease (MND) at any given time. MND is a lethal neurodegenerative disease that involves selective loss of motor neurons. Motor neurons are nerve cells that transmit signals from the brain to muscles (e.g. to move a finger). They have a cell body and long threadlike extensions that connect to muscles. These extensions are called axons. In MND the axons break down and because of that the connection between the brain and muscles gets lost. This causes progressive muscle weakness and wasting that ends in paralysis, inability to speak or swallow and in the end stops breathing. Riluzole is currently the only drug licensed for treating MND in the UK. Although riluzole may moderately increase survival, it is not a cure, and will not repair any damage to motor neurons that is already present when the patient starts taking riluzole. To develop better therapies for MND, we need to understand the causes of the disease much better. The research we propose here is to find out the events that lead up to motor neuron death in MND.Our research concentrates on finding out how the axons of motor neurons break down in MND because this is one of the first things that is seen in laboratory models of the disease. We concentrate particularly on a process called "axonal transport". Most axonal building blocks are manufactured in the cell body and have to be delivered to their destinations in the axon. This "delivery service" is called axonal transport. Technically axonal transport is rather like a train journey: Molecular motors ("the locomotives") hook up to cargoes ("the carriages"), and they ride on protein tracks called microtubules ("the rails") and burn "a fuel" called ATP to do so. When axonal transport breaks down the axon starves because no deliveries are being made, and eventually the nerve dies. We have found that axonal transport of one particular cargo called mitochondria is defective in MND. Mitochondria are very important for nerves because they produce the ATP fuel needed to power everything; in other words mitochondria are the power stations of the cell. In MND the breakdown of the transport system leads to fewer mitochondria in the axon and this is likely to cause axons to die because of lack of fuel. What we don't know exactly is what causes this breakdown. Like the train journey, defects in axonal transport can be via a number of routes: Maybe an essential component is missing? Are "the locomotives" (molecular motors) damaged or do they lack "fuel" (ATP)? Is the connection between "the carriages" (mitochondria) and the locomotives broken? Are "the rails" (microtubules) disrupted? Or, is there signal failure? We already know that in one inherited form of MND a surplus in the signalling molecule calcium causes defective transport of mitochondria. In this project we want to investigate if this is also the case in other forms of MND to see if this is a defect that is common to all MND. We also want to investigate how calcium stops transport. Once we find out exactly how this defect is caused, we will try to prevent the defect or restore transport, and measure if this protects motor neurons from dying.Summarised, this research will investigate the events leading up to a key event in MND, with the potential for future drug development. Furthermore, because axonal transport defects are also seen in other neurodegenerative diseases, including Alzheimer's and Parkinson's disease the results are likely to be informative about those diseases as well.