权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

蛋白质 SUMO 化在 AMPA 受体运输、突触功能障碍和痴呆认知障碍中的作用

基本信息

批准号：
MR/L003791/1
负责人：
Jeremy Henley
金额：
$ 146.89万
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：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL003791%2F1
关键词：
Roles protein SUMOylation AMPA receptor

项目摘要

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.

美国国立卫生研究院将痴呆症定义为“一组大脑疾病，可以剥夺患者进行正常活动的能力，例如穿衣或吃饭。他们可能会失去解决问题或控制情绪的能力。他们的性格可能会改变。他们可能会变得焦躁不安或看到不存在的东西。“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。据估计，仅AD就影响了全球约4000万人，英国约50万人，造成了毁灭性的个人和社会后果，每年造成的损失超过230亿英镑。痴呆症是一种进行性的、与年龄相关的、目前无法治愈的疾病，但已经取得了显着的进展，并且一直在不断有新的发现。尽管仍有许多障碍需要克服，但有真实的希望，了解痴呆症的原因将导致更有针对性的治疗和方法，以防止在可预见的未来疾病。大脑由数十亿个神经细胞组成，它们通过称为突触的间隙相互传递化学信号。突触通过接收细胞上的专门受体蛋白来工作，检测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通讯。在痴呆症的早期阶段，细胞之间的这种信号传递出错，我们认为这是因为AMPA受体没有正确定位以接收神经递质信号。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）的机制从繁忙的忙碌中移除。这是一个严格控制的过程，在其他时间通过AMPA受体的替换来平衡，以确保突触能够接受新的信号。在痴呆症中，这个过程中的“制衡”停止工作，太多的AMPAR受体被移除，而不是被取代。因为突触必须保持活跃，AMPA受体的丢失会导致突触退化，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症中控制突触AMPA受体的过程出现了什么问题。我们的假设是，AMPA受体的正确靶向和锚定需要一个称为SUMO化的过程的参与。这是一种叫做SUMO的小蛋白质附着在靶蛋白上并改变其特性的时候。在过去的几年中，已经表明SUMO化在包括癌症和中风在内的许多疾病中起着重要作用，并且它与帕金森氏病、精神发育迟滞和阿尔茨海默氏病密切相关。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功能障碍。