Understanding the roles of SUMO proteases in neuronal function and viability

研究背景神经细胞通过在称为突触的微小结构上传递化学信号来相互交谈。每个神经细胞大约有10,000个突触，每个突触都会根据其所处的环境不断改变信息传输的效率。例如，当我们学习一些突触时，效率会变得更高，当我们记住时，效率的提高就会稳定下来。另一方面，突触效率的丧失是与年龄相关的认知衰退和痴呆症的原因。突触的信息传递发生在突触前细胞释放神经递质时，突触后细胞表面的受体检测到神经递质。如果在足够多的突触上激活了足够多的受体，接收神经细胞就会重复这一过程并传递信息。所有这些协调工作的过程对大脑的正常工作至关重要。目的和目的本项目的目的是更好地了解神经细胞中控制突触传递的蛋白质是如何调节的，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被称为SUMO化的过程，特别是通过反向过程去SUMO化而改变非常感兴趣。当一种小的蛋白质，即相扑，与另一种“靶”蛋白偶联，从而改变靶蛋白的功能时，相扑就发生了。我们已经证明，蛋白质SUMO化显著影响关键突触蛋白。然而，人们对其去SUMO的过程和机制知之甚少。这一点很重要，因为我们最新的工作表明，适当控制的去SUMO化对于确定突触在不同条件下的反应至关重要，例如学习或中毒情况。为了了解更多，我们打算专注于两种主要的酶，称为SENP1和SENP3，它能使目标蛋白脱SUMO。我们想要测试的想法是，SENP1和SENP3的去SUMO活性在大脑中受到严格控制，并且它们被准确地定位在需要的时间和地点。我们还认为，当神经细胞需要维持特定目标蛋白质组的SUMO化时，附近的SENPs会迅速失活并被分解，以便实现这一点。虽然我们已经知道一些SENP1和SENP3去SUMOylate的蛋白质，但这只是它们调控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，我们想要准确地找出哪些蛋白质调节SENP1和SENP3，以及哪些蛋白质受SENP1和SENP3调节。这些信息将提供对这些SENPs控制哪些途径和过程的洞察，并将更清晰地描述我们如何设计策略来操纵它们以实现潜在的治疗益处。潜在的应用和好处这项建议直接属于BBRSC任务的范围，因为大量的临床、遗传和生化证据表明，类似的核心分子途径是衰老和一系列疾病的基础。我们认为去SUMO化是这些核心途径之一，这项工作是新颖的、令人兴奋的和重要的，因为它直接解决了突触如何运作的问题。增加对正常健康细胞中这些过程的了解，将为什么可能出现问题以及如何修复提供有价值的新信息。

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.