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TRAK-mediated neuronal mitochondrial trafficking mechanisms: regulation and impact on neuronal function

TRAK介导的神经元线粒体运输机制：对神经元功能的调节和影响

基本信息

批准号：
BB/K014285/1
负责人：
Frances Stephenson
金额：
$ 82.18万
依托单位：
University College London
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=BB%2FK014285%2F1
关键词：
TRAK mediated neuronal mitochondrial trafficking

项目摘要

Information in our brains is processed by a network of specialized cells, neurons. Neurons are asymmetric. Each has a cell body from which processes known as axons and dendrites emerge. Axons transmit information to other neurons by forming connections (synapses) onto cell bodies or dendrites. Dendrites are extensive processes that receive information from axons. Synaptic transmission, information transfer from axon terminal to dendrites, requires particular proteins and energy in the form of the molecule, ATP. Further the transfer of information from dendrites to cell bodies also requires special proteins and energy. New proteins are mostly synthesized in cell bodies so they have to be trafficked to their correct location. This is transport. It is important for movement of newly synthesized proteins and trafficking of organelles such as mitochondria, the ATP supply of cells. The components of transport are kinesins (motor proteins) which travel along the microtubular network ferrying their cargoes, proteins and organelles. The kinesins do not bind directly to their cargoes but employ adaptor proteins. At any one time, ~ 30% of neuronal mitochondria are mobile moving towards (anterograde) and away from (retrograde) synapses. Mitochondria need to be able to translocate rapidly to areas of high energy demand (synapses) and once there, need to be anchored or "parked". Until recently, we did not know the identity of any of the players that are involved in moving mitochondria. Significant advances have now been made. The Stephenson group identified a family of proteins, the TRAKs, which are the major adaptors involved in their anterograde transport. She used advanced imaging methods to visualize moving mitochondria in axons in cultured neuronal cells and showed that TRAKs are important for mitochondrial movement. TRAKs are present in dendrites too where they are likely to be involved in mitochondrial motility. Having discovered the function of this important family of proteins, we now want to determine the importance of this for proper neuronal function (synaptic transmission and dendritic information processing) in the brain. We plan to investigate this using acute brain slices obtained from adult rodent brain where neuronal network activity is retained together with state-of the art techniques such as electrophysiological recordings from single cells and two photon imaging. We also want to understand further how TRAK-mediated mitochondrial transport is regulated. We have found that an enzyme, N-acetylglucosamine transferase (OGT), is another component of the TRAK/kinesin mitochondrial trafficking complex. OGT is a nutrient sensor. This means that its activity is regulated by metabolic demands. It modifies proteins by addition of a sugar, N-acetylglucosamine. Since mitochondria supply energy it is not unreasonable to hypothesize that the activity of this enzyme may regulate the formation of the kinesin/TRAK/mitochondrial complex to enable mitochondria to traffic to respond to local energy requirements. These are important questions since many neurodegenerative diseases, for example Alzheimer's disease, motor neuron disease and Huntington's disease, for which there are currently no effective treatments have deficits with respect to mitochondrial distribution and function. Deficits in mitochondrial trafficking i.e. appropriate availability of energy sources may be early events compromising neuronal function eventually contributing or even being causal to these diseases. Understanding these basic trafficking mechanisms may contribute towards development of innovative therapies for their treatment.

我们大脑中的信息是由专门的细胞和神经元组成的网络来处理的。神经元是不对称的。每个细胞都有一个细胞体，从中产生了称为轴突和树突的过程。轴突通过在细胞体或树突上形成连接(突触)将信息传递给其他神经元。树突是从轴突接收信息的广泛过程。突触传递，即从轴突末端到树突的信息传递，需要以分子ATP的形式存在的特殊蛋白质和能量。此外，从树突到细胞体的信息传递也需要特殊的蛋白质和能量。新的蛋白质大多是在细胞体中合成的，因此它们必须被运送到正确的位置。这是交通工具。它对新合成的蛋白质的运动和细胞器的运输，如线粒体，细胞的三磷酸腺苷供应非常重要。运输的组成部分是运动蛋白(马达蛋白)，它们沿着微管网络运输它们的货物、蛋白质和细胞器。动蛋白并不直接与它们的货物结合，而是使用接头蛋白。在任一时刻，约30%的神经元线粒体向(顺行)和远离(逆行)突触移动。线粒体需要能够迅速转移到能量需求高的区域(突触)，一旦到达那里，就需要锚定或“停放”。直到最近，我们还不知道参与线粒体移动的任何参与者的身份。现在已经取得了重大进展。斯蒂芬森研究小组确定了一个蛋白质家族--Traks，它们是参与顺行运输的主要适配器。她使用先进的成像方法对培养的神经细胞轴突中运动的线粒体进行了可视化，并表明Traks对线粒体运动非常重要。TRAK也存在于树突中，它们可能参与线粒体的运动。在发现了这一重要蛋白质家族的功能后，我们现在想确定它对大脑中正常的神经元功能(突触传递和树突信息处理)的重要性。我们计划使用从成年啮齿动物大脑中获得的急性脑片来研究这一点，在成年啮齿动物大脑中，神经元网络活动保持在一起，并使用最先进的技术，如单细胞电生理记录和双光子成像。我们还想进一步了解TRAK介导的线粒体运输是如何调控的。我们发现，N-乙酰氨基葡萄糖转移酶(OGT)是TRAK/Kinesin线粒体运输复合体的另一个组成部分。OGT是一种营养传感器。这意味着它的活动受到新陈代谢需求的调节。它通过添加一种糖，N-乙酰氨基葡萄糖来修饰蛋白质。由于线粒体提供能量，因此假设该酶的活性可能调节Kinesin/TRAK/线粒体复合体的形成，从而使线粒体能够对局部能量需求做出反应，这并不是不合理的。这些都是重要的问题，因为许多神经退行性疾病，如阿尔茨海默病、运动神经元病和亨廷顿病，目前还没有有效的治疗方法，但在线粒体分布和功能方面存在缺陷。线粒体运输的缺陷，即能源的适当可获得性，可能是损害神经元功能的早期事件，最终导致或甚至导致这些疾病。了解这些基本的贩运机制可能有助于开发治疗这些疾病的创新疗法。