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

我们大脑中的信息是由一个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终末被称为突触的特殊区域。突触是代谢动态的，需要不断补充能量和蛋白质，以确保大脑功能的保真度。由于突触通常离神经元细胞体较远（最远可达1米），新合成的蛋白质需要被运送到这些活跃区域。这种运输过程是由运动蛋白通过在神经元内的微管网络中移动的接头蛋白与它们的货物相关联来实现的。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TRAK2)，它是这些运输过程中不可或缺的一个新基因家族的成员。这个名字来源于GRIF-1在抑制性GABA-A神经递质受体蛋白向突触的运输中首次发现的功能作用，但现在认为它在神经元运输过程中起着更普遍的作用，因为它已被证明与运动蛋白激酶相关。在经常被用作模式生物的苍蝇中，研究人员发现了一种类似于GRIF-1的蛋白质。这种蛋白质叫做米尔顿。这个名字来源于盲人诗人约翰·弥尔顿；没有弥尔顿的苍蝇是瞎的。在这些突变的果蝇中，研究人员发现，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突触中缺失。由此推测，弥尔顿在将这些细胞器运送到突触中发挥了重要作用，为相邻神经元之间的适当交流提供能量。在本研究计划中，我们希望研究GRIF-1 （TRAK2）和相关蛋白OIP106 （TRAK1）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Milton相似的功能；以确定哪些线粒体蛋白GRIF-1和OIP106结合，并确定它们的活性是如何被调节的。贩运机制的缺乏可能导致神经退行性疾病的病理，如阿尔茨海默病和痉挛。因此，如果我们了解了这些基本机制，将来就有可能为开发治疗这些疾病的创新疗法做出贡献。

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.