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，每个突触都根据其环境不断改变信息传递的效率。例如，当我们学习时，一些突触变得更有效率，当我们记住这种效率的增加是稳定的。另一方面，突触效率的丧失是与年龄相关的认知能力下降和痴呆的原因。当突触前细胞释放的神经递质被突触后细胞表面的受体检测到时，突触处的信息传递发生。如果在足够的突触上有足够的受体被激活，接收信号的神经细胞就会重复这个过程并传递信息。所有这些过程协调工作对于大脑正常工作至关重要。本研究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被称为SUMO化的过程所改变非常感兴趣，特别是通过反向过程去SUMO化。当一个小蛋白SUMO与另一个“靶”蛋白偶联以改变靶蛋白的功能时，发生SUMO化。我们已经表明，蛋白质SUMO化显着影响关键的突触蛋白。然而，很少有人知道他们的去SUMO化的过程和机制。这一点很重要，因为我们最近的工作表明，适当控制的去SUMO化在确定突触在不同条件下（如学习或中毒情况）的反应方面至关重要。为了了解更多，我们打算专注于两种主要的酶，称为SENP 1和SENP 3，它们使靶蛋白去SUMO化。我们想验证SENP1和SENP3的去SUMO化活动在大脑中受到严格控制，并且它们在需要的时候和地方被精确定位。我们还认为，当神经细胞需要维持特定靶蛋白组的SUMO化时，附近的SENP会迅速失活并分解，以实现这一目标。虽然我们已经知道SENP 1和SENP 3去SUMO化的一些蛋白质，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，我们希望精确地找出哪些蛋白质调节SENP1和SENP3，以及由SENP1和SENP3调节。这些信息将提供对这些SENP控制哪些途径和过程的深入了解，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。潜在的应用和益处遗传和生物化学证据表明，相似的核心分子途径是衰老和多种疾病的基础。我们相信去SUMO化是这些核心通路之一，这项工作是新颖的，令人兴奋的和重要的，因为它直接解决了关于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可能出现的错误以及如何修复它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.