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

Miro 和 PKC 信号在肌萎缩侧索硬化症轴突运输缺陷中的作用。

• 批准号: MR/K005146/1
• 负责人: Kurt De Vos
• 金额: $ 53.87万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK005146%2F1
• 关键词: role; Miro; PKC; signalling; axonal

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.

在英国，大约有6,000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。运动神经元是将信号从大脑传递到肌肉（例如移动手指）的神经细胞。它们有一个细胞体和连接肌肉的长丝状延伸部分。这些延伸被称为轴突。在MND中，轴突断裂，因此大脑和肌肉之间的连接丢失。这会导致进行性肌肉无力和消瘦，最终导致瘫痪，无法说话或吞咽，最终停止呼吸。阿曲唑是目前英国唯一获准用于治疗MND的药物。虽然利鲁唑可能会适度增加生存率，但它不是一种治愈方法，并且不会修复患者开始服用利鲁唑时已经存在的运动神经元的任何损伤。为了开发更好的治疗MND的方法，我们需要更好地了解疾病的原因。我们在这里提出的研究是找出导致MND运动神经元死亡的事件。我们的研究集中在找出MND运动神经元轴突如何分解，因为这是在该疾病的实验室模型中首先看到的事情之一。我们特别关注一个叫做“轴突运输”的过程。大多数轴突构建模块在细胞体中制造，并且必须被递送到轴突中的目的地。这种“传递服务”被称为轴突运输。从技术上讲，轴突运输就像火车旅行：分子发动机（“火车头”）连接到货物（“车厢”）上，它们行驶在称为微管（“铁轨”）的蛋白质轨道上，并燃烧称为ATP的“燃料”。当轴突运输中断时，轴突会因为没有传递而挨饿，最终神经死亡。我们已经发现，轴突运输一个特定的货物称为线粒体是有缺陷的MND。线粒体对神经非常重要，因为它们产生为一切提供动力所需的ATP燃料;换句话说，线粒体是细胞的发电站。在MND中，运输系统的崩溃导致轴突中的线粒体减少，这可能导致轴突因缺乏燃料而死亡。我们不知道到底是什么导致了这种崩溃。就像火车旅行一样，轴突运输的缺陷可以通过许多途径：也许缺少一个重要的组成部分？是“火车头”（分子发动机）受损，还是缺乏“燃料”（ATP）？“车厢”（线粒体）和火车头之间的连接是否中断？“铁轨”（微管）被破坏了吗？还是信号故障？我们已经知道，在一种遗传形式的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，我们想调查这是否也是其他形式的MND的情况，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转运的。一旦我们确切地发现这种缺陷是如何引起的，我们将尝试阻止缺陷或恢复运输，并测量这是否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，并有可能用于未来的药物开发。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氏病，因此结果也可能是关于这些疾病的信息。

项目成果

SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.

• DOI: 10.1038/ncomms16063
• 发表时间: 2017-07-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hautbergue GM;Castelli LM;Ferraiuolo L;Sanchez-Martinez A;Cooper-Knock J;Higginbottom A;Lin YH;Bauer CS;Dodd JE;Myszczynska MA;Alam SM;Garneret P;Chandran JS;Karyka E;Stopford MJ;Smith EF;Kirby J;Meyer K;Kaspar BK;Isaacs AM;El-Khamisy SF;De Vos KJ;Ning K;Azzouz M;Whitworth AJ;Shaw PJ
• 通讯作者: Shaw PJ

Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

• DOI: 10.1016/j.nbd.2015.10.007
• 发表时间: 2016-01
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Rodríguez-Martín T;Pooler AM;Lau DHW;Mórotz GM;De Vos KJ;Gilley J;Coleman MP;Hanger DP
• 通讯作者: Hanger DP

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.

• DOI: 10.1038/ncomms4996
• 发表时间: 2014-06-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Stoica, Radu;De Vos, Kurt J.;Paillusson, Sebastien;Mueller, Sarah;Sancho, Rosa M.;Lau, Kwok-Fai;Vizcay-Barrena, Gema;Lin, Wen-Lang;Xu, Ya-Fei;Lewis, Jada;Dickson, Dennis W.;Petrucelli, Leonard;Mitchell, Jacqueline C.;Shaw, Christopher E.;Miller, Christopher C. J.
• 通讯作者: Miller, Christopher C. J.

Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?

• DOI: 10.1016/j.nbd.2017.02.004
• 发表时间: 2017-09
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: De Vos KJ;Hafezparast M
• 通讯作者: Hafezparast M

Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.

• DOI: 10.1038/ncomms6245
• 发表时间: 2014-10-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Godena, Vinay K.;Brookes-Hocking, Nicholas;Moller, Annekathrin;Shaw, Gary;Oswald, Matthew;Sancho, Rosa M.;Miller, Christopher C. J.;Whitworth, Alexander J.;De Vos, Kurt J.
• 通讯作者: De Vos, Kurt J.