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OIP106 (TRAK1) and GRIF-1 (TRAK2) kinesin-associated adaptor proteins: a study of their role in mitochondrial trafficking processes in neurones

OIP106 (TRAK1) 和 GRIF-1 (TRAK2) 驱动蛋白相关接头蛋白：研究它们在神经元线粒体运输过程中的作用

基本信息

批准号：
BB/E021549/1
负责人：
Frances Stephenson
金额：
$ 50.99万
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：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE021549%2F1
关键词：
OIP106 TRAK1 GRIF TRAK2 kinesin

项目摘要

Information in our brains is processed by a discontinuous network of nerve cells or neurones. Communication between these cells occurs at specialized regions called synapses that are found at axon terminals. Synapses are metabolically dynamic and energy sources and proteins need to be constantly replenished to ensure fidelity of brain function. Since the synapse is often distant from the neuronal cell body (it can be up to 1 metre away), newly synthesized proteins need to be transported to these active zones. This transport process is achieved by motor proteins that associate with their cargoes via adaptor proteins that travel along the microtubular network within the neurones. My research group discovered a protein, GABA-A Receptor Interacting Factor-1 (GRIF-1, also called TRAK2), a member of a new gene family that is integral to these transport processes. The name derives from GRIF-1's first identified functional role in the transport of inhibitory GABA-A neurotransmitter receptor proteins to synapses but, it is now thought to play a more general role in neuronal trafficking processes since it has been shown to associate with the motor protein, kinesin. In flies, often used as model organisms, researchers have identified a protein that is similar to GRIF-1. This protein is called Milton. The name derives from the blind poet, John Milton; flies that do not have Milton are blind. In these mutant flies, it was found that mitochondria, a subcomponent of the cell that supplies energy, are absent from synapses in the neurones in the eyes of flies. It was thus speculated that Milton plays an important role in the trafficking of these organelles to synapses to supply energy for the proper communication between adjacent neurones. In this research proposal, we wish to study the role of GRIF-1 (TRAK2) and the related protein OIP106 (TRAK1) in model cell systems and in neurones to test if they have a similar function to Milton; to identify which mitochondrial proteins GRIF-1 and OIP106 bind and to determine how their activities are regulated. A deficiency in trafficking mechanisms may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease and spasticity. Thus, if we understand these basic mechanisms, in the future it may be possible to contribute towards the development of innovative therapies for their treatment.

我们大脑中的信息是由不连续的神经细胞或神经元网络处理的。这些细胞之间的交流发生在轴突末端称为突触的专门区域。突触是代谢动态的，能量来源和蛋白质需要不断补充，以确保大脑功能的保真度。由于突触通常远离神经元细胞体（最远可达1米），新合成的蛋白质需要被运送到这些活性区。这一转运过程是通过马达蛋白实现的，马达蛋白通过接头蛋白与它们的货物结合，接头蛋白沿着神经元内的微管网络沿着。我的研究小组发现了一种蛋白质，GABA-A受体相互作用因子-1（GRIF-1，也称为TRAK 2），这是一个新的基因家族的成员，是这些运输过程中不可或缺的。该名称源于GRIF-1在将抑制性GABA-A神经递质受体蛋白转运到突触中的首次鉴定的功能作用，但是现在认为它在神经元运输过程中发挥更普遍的作用，因为它已被证明与运动蛋白驱动蛋白相关。在通常用作模式生物的苍蝇中，研究人员已经确定了一种与GRIF-1相似的蛋白质。这种蛋白质叫做米尔顿。这个名字来自盲人诗人约翰米尔顿;苍蝇没有米尔顿是盲目的。在这些突变的果蝇中，发现线粒体，一种提供能量的细胞的子成分，在果蝇眼睛的神经元中的突触中缺失。因此推测，米尔顿在将这些细胞器运输到突触以提供相邻神经元之间适当通信的能量方面起着重要作用。在这项研究计划中，我们希望研究GRIF-1（TRAK 2）和相关蛋白OIP 106（TRAK 1）在模型细胞系统和神经元中的作用，以测试它们是否具有与米尔顿相似的功能;识别哪些线粒体蛋白GRIF-1和OIP 106结合，并确定它们的活性是如何调节的。运输机制的缺陷可能导致神经退行性疾病如阿尔茨海默病和痉挛的病理学。因此，如果我们了解这些基本机制，将来可能有助于开发治疗它们的创新疗法。