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

我们大脑中的信息是由一个专门的细胞网络处理的，神经元。神经元是不对称的每一个都有一个细胞体，从细胞体中出现被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，即信息从轴突末端传递到树突，需要特定的蛋白质和以分子ATP形式存在的能量。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。新的蛋白质主要是在细胞体内合成的，所以它们必须被运送到正确的位置。这是运输。它对于新合成的蛋白质的运动和细胞器如线粒体的运输，细胞的ATP供应是重要的。运输的组分是驱动蛋白（马达蛋白），其沿着微管网络运送其货物、蛋白质和细胞器。驱动蛋白不直接与其货物结合，而是利用衔接蛋白。在任何时候，约30%的神经元线粒体是移动的，朝向（顺行）和远离（逆行）突触移动。线粒体需要能够迅速转移到高能量需求的区域（突触），一旦到达那里，就需要锚定或“停泊”。直到最近，我们还不知道参与移动线粒体的任何参与者的身份。现已取得重大进展。斯蒂芬森小组鉴定了一个蛋白质家族，TRAK，它是参与其顺行运输的主要衔接子。她使用先进的成像方法来可视化培养的神经元细胞轴突中移动的线粒体，并表明TRAKs对线粒体运动很重要。TRAK也存在于树突中，它们可能参与线粒体运动。在发现了这个重要的蛋白质家族的功能之后，我们现在想确定它对大脑中适当的神经元功能（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切片来研究这一点，其中神经元网络活动与最先进的技术如单细胞电生理记录和双光子成像一起保留。我们还想进一步了解TRAK介导的线粒体转运是如何调节的。我们已经发现，一种酶，N-乙酰葡糖胺转移酶（OGT），是TRAK/驱动蛋白线粒体运输复合物的另一个组成部分。OGT是一种营养传感器。这意味着它的活性受代谢需求的调节。它通过添加糖N-乙酰葡糖胺来修饰蛋白质。由于线粒体提供能量，因此假设这种酶的活性可以调节驱动蛋白/TRAK/线粒体复合物的形成以使线粒体能够运输以响应局部能量需求并非不合理。这些都是重要的问题，因为许多神经变性疾病，例如阿尔茨海默病、运动神经元病和亨廷顿病，目前没有有效的治疗方法，在线粒体分布和功能方面存在缺陷。线粒体运输的缺陷，即能量来源的适当可用性可能是损害神经元功能的早期事件，最终促成或甚至是这些疾病的原因。了解这些基本的贩运机制可能有助于开发治疗这些人的创新疗法。

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.