Roles of protein SUMOylation in AMPA receptor trafficking, synaptic dysfunction and cognitive impairment in dementia

美国国立卫生研究院将痴呆症定义为“一组大脑疾病，这些疾病会剥夺患者进行正常活动的能力，比如穿衣服或吃饭。他们可能会失去解决问题或控制情绪的能力。他们的个性可能会改变。他们可能会变得焦躁不安，或者看到不存在的东西。”痴呆症最常见的原因是阿尔茨海默病(AD)，约占所有痴呆症的65%，典型的发病年龄为65岁。仅AD一项就影响了全球约4000万人和英国约50万人，造成了毁灭性的个人和社会后果，每年花费超过230亿GB。痴呆症是一种渐进性的、与年龄相关的疾病，目前无法治愈，但已经取得了显著的进展，而且一直有新的发现。尽管仍有许多障碍需要克服，但在可预见的未来，了解痴呆症的原因将导致更有针对性的治疗和预防疾病的方法，这是真正的希望。大脑由数十亿个神经细胞组成，这些神经细胞通过称为突触的缝隙相互传递化学信号。突触通过在接收细胞上的特殊受体蛋白来工作，检测从发送神经细胞释放的化学递质。最重要的神经递质受体蛋白之一是AMPA受体，它负责大脑中几乎所有的快速交流。在痴呆症的早期阶段，细胞之间的这种信号传递出现了错误，我们认为这是因为AMPA受体没有正确定位来接收神经递质信号。在高度活跃的正常神经细胞中，一些AMPA受体通过一种称为长期抑制(LTD)的机制从繁忙的突触中移除。这是一个严格控制的过程，在其他时候通过替换AMPA受体来平衡，以确保突触接受新的信号。在痴呆症中，这个过程中的“制衡”机制停止工作，太多的AMPAR受体被移除，它们没有被替换。因为突触必须保持活跃才能维持，这种AMPA受体的丧失会导致突触退化，最终导致神经细胞死亡。随着越来越多的连接丢失和神经细胞死亡，大脑失去了正常工作的能力。我们工作的目的是找出痴呆患者控制突触AMPA受体的过程出了什么问题。我们的假设是，AMPA受体的正确靶向和锚定需要一个称为SUMO化的过程。这是一种名为相扑的小蛋白质附着在目标蛋白质上并改变其特性的时候。在过去的几年中，研究表明，SUMO化在包括癌症和中风在内的许多疾病中发挥着重要作用，并与帕金森氏症、智力低下和阿尔茨海默病密切相关。我们最近发现，SUMO化在控制正常神经细胞中的AMPA受体方面起着关键作用，我们打算研究它在痴呆症中是如何失败的，以及我们可以做些什么来纠正这种功能障碍。

The National Institutes of Heath in the USA define dementia as "a set of brain diseases that can deprive patients of the ability to think well enough to do normal activities, such as getting dressed or eating. They may lose their ability to solve problems or control their emotions. Their personalities may change. They may become agitated or see things that are not there." The most common cause of dementia is Alzheimer's disease (AD), which accounts for about 65% of all dementia, has a typical onset age of 65. AD alone affects an estimated 40 million people in the world and about 0.5 million in the UK with devastating personal and social consequences, and an annual cost of more than £23 billion.Dementia is a progressive, age-related and currently incurable disease but remarkable progress has been achieved and new discoveries are being made all of the time. Although there are still many hurdles to overcome, there is real hope that understanding the causes of dementia will lead to more targeted treatments and ways to prevent the disease in the foreseeable future. The brain is composed of billions of nerve cells, which pass chemical signals to each other across gaps called synapses. Synapses work by specialised receptor proteins on the receiving cell detecting chemical transmitters released from the sending nerve cell. One of the most important types of neurotransmitter receptor protein is the AMPA receptor, which are responsible for nearly all of the fast communication in the brain. In the early stages of dementia this signalling between cells goes wrong and we believe that this is because AMPA receptors are not correctly positioned to receive neurotransmitter signals. In highly active normal nerve cells some of the AMPA receptors are removed from busy synapses by a mechanism called long-term depression (LTD). This is a tightly controlled process that is balanced by the replacement of AMPA receptors at other times to make sure the synapse is receptive to new signals. In dementia the 'checks and balances' in this process stops working and too many AMPAR receptors are removed and they are not replaced. Because synapses have to be active to be maintained, this loss of AMPA receptors causes the synapse to degenerate and eventually the nerve cell to die. As more and more connections are lost and nerve cells die the brain loses the ability for work properly.The purpose of our work is to find out what goes wrong with the processes controlling synaptic AMPA receptors in dementia. Our hypothesis is that the proper targeting and anchoring of AMPA receptors requires the involvement of a process called SUMOylation. This is when a small protein called SUMO attaches to a target protein and changes its characteristics. In the past few years it has been shown that SUMOylation plays major roles in many diseases including cancer and stroke, and it has been strongly implicated in Parkinson's disease, mental retardation and Alzheimer's disease. We recently discovered that SUMOylation plays a key role in controlling AMPA receptors in normal nerve cells and we intend to investigate how it fails in dementia and what we can do to correct the dysfunction.