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.

神经细胞通过传递突触的信息来通信。突触是在轴突之间形成的结构，轴突将信息从神经细胞中传递出来，并将其接收到细胞中的信息。通常，突触的形成需要轴突的生长和伸长才能找到其他细胞的树突。这个过程听起来很简单，但实际上，它需要一系列高度调节和协调的事件。首先需要发生的第一件事是，细胞必须指定哪个突出将是轴突，哪些将是树突。该过程称为极化，通常会导致单个长轴突和较小的树突。调节神经元极化和随后的轴突生长的分子事件尚不清楚。但是，很明显，蛋白质的靶向破坏是重要的因素。例如，某些蛋白质的主要功能是阻止其他蛋白质的作用。只有在第一种蛋白质破坏时，第二蛋白才能发挥其作用。细胞破坏蛋白质的主要方式是用称为泛素的小标记蛋白标记它们。泛素标签充当识别剂，可以将这些蛋白质募集到蛋白酶体中，该结构分解并回收有害的蛋白质。我们最近发现，仅存在于神经元中的蛋白质UCH-L1在调节蛋白质的泛素标记方面起着关键作用，其一种作用是增强轴突生长。我们的目的是了解UCH-L1是如何做到这一点，涉及其他蛋白质以及出现问题时会发生什么的。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形成网络的信息，这是大脑工作原理的基础。此外，UCH-L1与多种重要疾病有关，例如帕金森氏症和阿尔茨海默氏症疾病，因此对UCH-L1功能的更好理解可以提供一种设计药物来帮助治疗这些疾病的方法。