Understanding the roles of SUMO proteases in neuronal function and viability

了解 SUMO 蛋白酶在神经元功能和活力中的作用

基本信息

批准号：
BB/R00787X/1
负责人：
Jeremy Henley
金额：
$ 106.94万
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：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR00787X%2F1
关键词：
Understanding roles SUMO proteases neuronal

项目摘要

Context of Research Nerve cells 'talk' to each other by transmitting chemical signals at tiny structures called synapses. Each nerve cell has about 10,000 synapses, each of which is constantly changing the efficiency of information transfer depending on its circumstances. For example, when we learn some synapses become more efficient and when we remember this increase in efficiency is stabilised. On the other hand, loss of synaptic efficiency is responsible for age-associated cognitive decline and dementia. Information transfer at a synapse occurs when the presynaptic cell releases neurotransmitter that is detected by receptors on the surface of the postsynaptic cell. If enough receptors are activated at enough synapses, the receiving nerve cell will repeat the process and pass on the message. All of these processes working in harmony are vital for the brain to work properly. Aims and ObjectivesThe aim of this project is to better understand how the proteins that control synaptic transmission in nerve cells are regulated, and investigate the links between them. In particular, we are extremely interested in how the behaviour of individual proteins is changed by a process called SUMOylation and, especially, by the reverse process deSUMOylation. SUMOylation occurs when a small protein, SUMO, is coupled to another 'target' protein to alter the function of the target protein. We have shown that protein SUMOylation dramatically affects key synaptic proteins. However, very little is known about the processes and mechanisms of their deSUMOylation. This is important because our most recent work indicates that properly controlled deSUMOylation is critically important in determining how synapses respond under different conditions such as learning or toxic situations. To find out more we intend to focus on two major enzymes, called SENP1 and SENP3, that deSUMOylate target proteins. We want to test the idea that SENP1 and SENP3 deSUMOylating activity is tightly controlled in the brain and that they are positioned exactly when and where they are needed. We also think that when the nerve cell needs to maintain the SUMOylation of specific sets of target proteins, the SENPs in the vicinity are quickly inactivated and broken down in order to make this happen. Although we already know some of proteins that SENP1 and SENP3 deSUMOylate, this is only a tiny fraction of the total number of proteins they regulate. Therefore, in a second, but highly related, aspect of the project we want to find out precisely which proteins regulate, and are regulated by, SENP1 and SENP3. This information will provide insight into which pathways and processes these SENPs control, and will give a much clearer picture of how we can design strategies to manipulate them for potential therapeutic benefit.Potential applications and benefitsThis proposal is directly within the remit of the BBRSC mission because a wealth of clinical, genetic and biochemical evidence indicates that similar core molecular pathways underpin aging and a wide range of diseases. We believe that deSUMOylation is one of these core pathways and that this work is novel, exciting and important because it directly addresses questions about how synapses operate. Increased understanding of these processes in normal healthy cells will provide valuable new information for what can go wrong, and potentially how to fix it.

研究神经细胞的背景通过在称为突触的微小结构上传输化学信号来“交谈”。每个神经细胞都有大约10,000个突触，每个神经都在不断地改变信息转移的效率，具体取决于其情况。例如，当我们了解一些突触会变得更加有效时，当我们记得这种提高效率时。另一方面，突触效率的丧失导致与年龄相关的认知能力下降和痴呆症。当突触前细胞释放神经递质的神经递质被受体在突触后细胞表面检测到的神经递质时，就会发生突触的信息传递。如果在足够的突触中激活足够的受体，则接收神经细胞将重复该过程并传递消息。所有这些以和谐工作的过程对于大脑正常工作至关重要。该项目的目的和客观性目的是更好地了解如何调节神经细胞中突触传播的蛋白质，并研究它们之间的联系。特别是，我们对单个蛋白质的行为如何通过称为sumoylation的过程，尤其是通过反向过程desumoylation更改。当将小蛋白Sumo耦合到另一个“靶”蛋白以改变靶蛋白的功能时，就会发生Sumoylation。我们已经表明，蛋白质磷酸化极大地影响了关键的突触蛋白。但是，对它们的淡化过程的过程和机制知之甚少。这很重要，因为我们最近的工作表明，正确控制的desumoylation在确定突触如何在不同条件（例如学习或有毒情况）下反应至关重要。为了了解更多信息，我们打算专注于两种称为SENP1和SENP3的主要酶，这些酶是desumoylate靶蛋白。我们想测试SENP1和SENP3 DESUMOYPIT活动在大脑中受到严格控制，并确切地定位在需要的时间和何处。我们还认为，当神经细胞需要维持特定靶蛋白的特定集合时，附近的SENP会很快灭活并分解，以实现这一目标。尽管我们已经知道一些蛋白质SENP1和SENP3 Desumoylate，但这只是它们调节的蛋白质总数的一小部分。因此，在该项目的第二个但高度相关的方面，我们希望准确地找出哪种蛋白质调节，并由SENP1和SENP3调节。该信息将提供有关这些途径和处理这些SENP的控制的信息，并将更清楚地了解我们如何设计策略来操纵它们以获得潜在的治疗益处。潜在的应用和福利直接在BBRSC任务的范围内，因为临床，遗传和生物化学的大量核心核心核心核心路径相似，并且较广泛的脂肪范围和敏捷量相似。我们认为Desumoylation是这些核心途径之一，这项工作是新颖，令人兴奋和重要的，因为它直接解决了有关突触如何运作的问题。对正常健康细胞中这些过程的了解将增加有价值的新信息，以解决可能出问题的问题，并有可能解决问题。