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

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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.