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Molecular and functional characterisation of the neuronal specific de-ubiquitinase UCH-L1 and its role in neuronal polarity and axonal outgrowth

神经元特异性去泛素酶 UCH-L1 的分子和功能表征及其在神经元极性和轴突生长中的作用

基本信息

批准号：
BB/K014366/1
负责人：
Jeremy Henley
金额：
$ 50.19万
依托单位：
University of Bristol
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%2FK014366%2F1
关键词：
Molecular functional characterisation neuronal specific

项目摘要

Nerves cell communicate by passing information across synapses. Synapses are structures formed between axons, which relay information out of the nerve cell, and dendrites, which receive information into the cell. In general, synapse formation requires the growth and elongation of axons to find dendrites of other cells. This process sounds simple but, in fact, it requires a highly regulated and coordinated series of events. One of the first things that need to happen is that the cell has to specify which protrusion will be an axon and which will be dendrites. This process is known as polarization and usually results in a single long axon and much smaller dendrites.The molecular events that regulate neuronal polarization and subsequent axonal outgrowth are not well understood. However, it is clear that the targeted destruction of proteins is an important factor. For example, the main function of some proteins is to block the effects of other proteins. It is only when the first protein is destroyed that the second protein can exert its effects. A major way cells destroy proteins is by tagging them with a small marker protein called ubiquitin. The ubiquitin tag acts as an identifier that allows these proteins to be recruited to the proteasome, a structure that breaks down and recycles unwanted proteins. We have recently discovered that UCH-L1, a protein that is only present in neurons, plays a key role in regulating the ubiquitin tagging of proteins and that one of its actions is to enhance axonal growth. Our aim is to understand how UCH-L1 does this, what other proteins are involved and what happens when it goes wrong. We believe that this is important because it will provide information about how nerve cells connect and how they form networks, which are the basis of how the brain works. In addition, UCH-L1 is associated with a number of important diseases, such as Parkinson's and Alzheimer's diseases, so better understanding of UCH-L1 function could provide a ways to design drugs to help treat these conditions.

神经细胞通过突触传递信息进行交流。突触是轴突和树突之间形成的结构，轴突将信息从神经细胞传递出去，树突将信息接收到细胞中。一般来说，突触的形成需要轴突的生长和伸长来寻找其他细胞的树突。这个过程听起来很简单，但实际上，它需要一系列高度规范和协调的活动。首先需要做的事情之一是，细胞必须指定哪个突起将是轴突，哪个突起将是树突。这个过程被称为极化，通常会导致单个长轴突和小得多的树突。调节神经元极化和随后轴突生长的分子事件还没有很好的理解。然而，很明显，蛋白质的靶向破坏是一个重要因素。例如，一些蛋白质的主要功能是阻止其他蛋白质的作用。只有当第一种蛋白质被破坏时，第二种蛋白质才能发挥作用。细胞破坏蛋白质的一种主要方式是用一种叫做泛素的小标记蛋白标记它们。泛素标签作为一个标识符，使这些蛋白质被招募到蛋白酶体，一个结构，打破和消除不需要的蛋白质。我们最近发现，UCH-L1是一种仅存在于神经元中的蛋白质，在调节蛋白质的泛素标记中起着关键作用，其作用之一是增强轴突生长。我们的目标是了解UCH-L1是如何做到这一点的，还有哪些其他蛋白质参与其中，以及当它出错时会发生什么。我们认为这很重要，因为它将提供有关神经细胞如何连接以及它们如何形成网络的信息，这些信息是大脑如何工作的基础。此外，UCH-L1与许多重要疾病有关，如帕金森病和阿尔茨海默病，因此更好地了解UCH-L1功能可以提供设计药物的方法来帮助治疗这些疾病。