Mechanisms and consequences of presynaptic protein SUMOylation in the regulation of neurotransmitter release

人脑被广泛认为是已知宇宙中最复杂的结构。尽管有如此巨大的复杂性，但在了解大脑中的单个细胞、它们如何沟通以及这种沟通如何被发展、经验、衰老和疾病改变方面，已经取得了显著的进展。大脑由神经元组成，神经元通过称为突触的特殊结构相互传递化学信号。突触是高度可塑性的，并且不断地经历信息传输效率的变化。正是这些可塑性的变化奠定了学习、记忆和认知的基础。另一方面，突触的有害变化导致了许多大脑疾病，包括与年龄相关的认知能力下降和痴呆症。突触由三个基本组成部分组成：突触前终端，它被电信号激活，并通过从称为囊泡的特殊结构中释放一种化学物质(神经递质)将其转换为化学信号；突触裂隙，神经递质通过它扩散；以及突触后膜，它包含检测神经递质的受体蛋白，并将化学信号转换回电信号。该项目旨在更好地了解突触前终末神经递质的释放过程。更具体地说，我们感兴趣的是一种名为SUMO化的过程，在这一过程中，一个小蛋白SUMO与另一种“靶”蛋白偶联，以改变其功能。我们已经证明，突触前末端的蛋白质SUMO化影响神经递质的释放量。在这项研究中，我们想要探索到底是哪些SUMOylated蛋白导致了这些释放的变化，以及这些变化是如何协调来调节突触功能的。我们打算把重点放在三种蛋白质上，它们已经被公认为神经递质释放过程的基本组成部分。重要的是，我们已经证实它们被相扑改变了，但效果完全未知。我们相信我们的工作是新的、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。进一步了解控制正常健康细胞神经递质释放的过程也将为衰老和疾病突触中可能出现的问题以及如何修复提供有价值的信息。

The human brain is widely considered to be the most complex structure in the known universe. Despite this massive complexity, remarkable progress has been achieved towards understanding individual cells of the brain, how they communicate and how this communication is modified by development, experience, aging and disease. The brain is composed of neurons, which pass chemical signals to each other via specialised structures called synapses. Synapses are highly plastic and constantly undergo changes in the efficiency of information transfer. It is these changes in plasticity that underlie learning, memory and cognition. On the other hand, detrimental changes in synapses are responsible for many brain diseases including age-associated cognitive decline and dementia. Synapses are composed of three basic components: the presynaptic terminal, which is activated by an electrical signal and converts this to a chemical signal by releasing a chemical (neurotransmitter) from the specialised structures called vesicles; the synaptic cleft, across which the neurotransmitter diffuses; and the postsynaptic membrane, which contains receptor proteins that detect the neurotransmitter and convert the chemical signal back to an electrical signal. This project seeks to better understand the processes of neurotransmitter release at the presynaptic terminal. More specifically we are interested in a process called SUMOylation, in which a small protein, SUMO, is coupled to another 'target' protein to alter its function. We have already shown that protein SUMOylation at the presynaptic terminal affects the amount of neurotransmitter release. In this study we want to explore exactly which SUMOylated proteins cause these changes in release and how these changes are coordinated to tune synaptic function. We intend to focus on three proteins that are already well established as fundamental components of the neurotransmitter release process. Importantly, we have validated that they are modified by SUMO but the effects are entirely unknown.We believe that our work is new, exciting and important because it directly addresses questions about how synapses operate. Increased understanding of the processes that control neurotransmitter release in normal healthy cells will also provide valuable information for what can go wrong, and potentially how to fix it, in aging and diseased synapses.