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.

美国国家医学院的国家研究所将痴呆症定义为“一组脑部疾病，可以使患者剥夺足够好的思考能力去做正常活动的能力，例如穿衣服或饮食。他们可能会失去解决问题或控制情绪的能力。他们的个性可能会发生变化。他们可能会变得烦躁或看到不存在的事物。”痴呆症的最常见原因是阿尔茨海默氏病（AD），约占所有痴呆症的65％，典型的发作年龄为65岁。仅AD就影响了世界上估计有4000万人，在英国，在英国有5000万人，在英国大约有50万人在个人和社会的危害中造成了灾难性的疾病，并且年龄增长了230亿英镑，而摄入量则超过了，但势不可及，并且持续不断地进步，并且持续不断，并且持续不断的势力，并且持续不断且富有元素的成果。一直在制作。尽管仍然有许多障碍要克服，但真正希望了解痴呆症的原因将导致更具针对性的治疗方法和防止这种疾病的方法。大脑由数十亿个神经细胞组成，这些神经细胞在称为突触的间隙之间相互传递化学信号。突触通过专门的受体蛋白在接收细胞上检测从发送神经细胞释放的化学发射器的接收细胞起作用。神经递质受体蛋白最重要的类型之一是AMPA受体，它几乎负责大脑中的所有快速通信。在痴呆症的早期阶段，这种细胞之间的信号传导出错，我们认为这是因为AMPA接收器未正确定位以接收神经递质信号。在高活性的正常神经细胞中，一些AMPA接收器通过一种称为长期抑郁症（LTD）的机制从繁忙的突触中删除。这是一个严格控制的过程，在其他时候可以通过更换AMPA接收器来平衡，以确保突触接受新信号。在痴呆症中，“检查和平衡”在此过程中停止工作，并且删除了太多的AMPAR接收器，并且未更换。由于必须保持突触必须保持活跃，因此AMPA接收器的这种丧失导致突触退化，最终导致神经细胞死亡。随着越来越多的连接丧失，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控制痴呆症中合成AMPA受体的过程出了问题。我们的假设是，适当的AMPA受体的靶向和锚定需要参与称为sumoylation的过程。这是一个称为SUMO的小蛋白附着在靶蛋白上并改变其特征的时候。在过去的几年中，Sumoylation在包括癌症和中风在内的许多疾病中都起着重要作用，并且在帕金森氏病，智力低下和阿尔茨海默氏病中已得到强有力的实施。我们最近发现，Sumoylation在控制正常神经细胞中的AMPA接收器中起着关键作用，我们打算研究其在痴呆症中的失败以及我们可以采取什么措施来纠正功能障碍。