Understanding the roles of SUMO proteases in neuronal function and viability

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Context of Research Nerve cells 'talk' to each other by transmitting chemical signals at tiny structures called synapses. Each nerve cell has about 10,000 synapses, each of which is constantly changing the efficiency of information transfer depending on its circumstances. For example, when we learn some synapses become more efficient and when we remember this increase in efficiency is stabilised. On the other hand, loss of synaptic efficiency is responsible for age-associated cognitive decline and dementia. Information transfer at a synapse occurs when the presynaptic cell releases neurotransmitter that is detected by receptors on the surface of the postsynaptic cell. If enough receptors are activated at enough synapses, the receiving nerve cell will repeat the process and pass on the message. All of these processes working in harmony are vital for the brain to work properly. Aims and ObjectivesThe aim of this project is to better understand how the proteins that control synaptic transmission in nerve cells are regulated, and investigate the links between them. In particular, we are extremely interested in how the behaviour of individual proteins is changed by a process called SUMOylation and, especially, by the reverse process deSUMOylation. SUMOylation occurs when a small protein, SUMO, is coupled to another 'target' protein to alter the function of the target protein. We have shown that protein SUMOylation dramatically affects key synaptic proteins. However, very little is known about the processes and mechanisms of their deSUMOylation. This is important because our most recent work indicates that properly controlled deSUMOylation is critically important in determining how synapses respond under different conditions such as learning or toxic situations. To find out more we intend to focus on two major enzymes, called SENP1 and SENP3, that deSUMOylate target proteins. We want to test the idea that SENP1 and SENP3 deSUMOylating activity is tightly controlled in the brain and that they are positioned exactly when and where they are needed. We also think that when the nerve cell needs to maintain the SUMOylation of specific sets of target proteins, the SENPs in the vicinity are quickly inactivated and broken down in order to make this happen. Although we already know some of proteins that SENP1 and SENP3 deSUMOylate, this is only a tiny fraction of the total number of proteins they regulate. Therefore, in a second, but highly related, aspect of the project we want to find out precisely which proteins regulate, and are regulated by, SENP1 and SENP3. This information will provide insight into which pathways and processes these SENPs control, and will give a much clearer picture of how we can design strategies to manipulate them for potential therapeutic benefit.Potential applications and benefitsThis proposal is directly within the remit of the BBRSC mission because a wealth of clinical, genetic and biochemical evidence indicates that similar core molecular pathways underpin aging and a wide range of diseases. We believe that deSUMOylation is one of these core pathways and that this work is novel, exciting and important because it directly addresses questions about how synapses operate. Increased understanding of these processes in normal healthy cells will provide valuable new information for what can go wrong, and potentially how to fix it.