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Understanding the roles of SUMO proteases in neuronal function and viability

Reference	BB/R00787X/1
Principal Investigator / Supervisor	Professor Jeremy Henley
Co-Investigators / Co-Supervisors	Dr Kevin Anthony Wilkinson
Institution	University of Bristol
Department	Biochemistry
Funding type	Research
Value (£)	839,255
Status	Current
Type	Research Grant
Start date	01/07/2018
End date	30/11/2023
Duration	65 months

Abstract

Context of Research The dynamic balance between SUMO conjugation, mediated by a restricted set of SUMOylation enzymes, and deSUMOylation mediated by SUMO proteases, controls substrate protein properties. Our recent discoveries indicate that targeted regulation of SUMO protease-mediated deSUMOylation is a critical factor in defining the extent and duration of substrate SUMOylation. Aims and Objectives Our lab is at the forefront of SUMO research in neurons. We have identified multiple synaptic and mitochondrial SUMO substrate proteins and established SUMOylation as a central regulator of synaptic function and plasticity, and of neuronal stress responses. In very recent, largely unpublished work, we show that the SUMO proteases SENP1 and SENP3 play defining roles in these processes. Our overarching hypothesis is that the spatially and temporally regulated deSUMOylation of target proteins, mediated by alterations of SUMO protease localization, levels or activity, is a fundamental mechanism controlling neuronal function and fate. Our core aims are to determine: 1. How are SENP1 and SENP3 regulated by synaptic activity? 2. How is synaptic transmission and plasticity regulated by SENP1 and SENP3? 3. How are SENP1 and SENP3 stability, activity and function regulated by posttranslational modifcations? 4. What proteins interact with SENP1 and SENP3? 5. Which specific target proteins mediate the synaptic affects of SENP1 and SENP3? Potential applications and benefits This research fits the remit of 'Healthy ageing across the lifecourse' because the regulation and dysregulation of SUMOylation and deSUMOylation are central to neuronal survival and synaptic function, and their dysfunction play major roles in age-related brain disorders. The mechanistic insight into how the balance between SUMOylation and deSUMOylation is controlled will identify new targets and open new avenues for design of innovative therapeutic interventions.

Summary

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 Objectives The 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 benefits This 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.

Impact Summary

Contribution to the BBSRC's strategic plan This proposal is 'world-class bioscience' and fits directly within the 'Lifelong Health and Wellbeing mission' and the Strategic research priority 3, 'Bioscience for Health'. Who might benefit from this research? Our aims are to understand the regulation and physiologica,l and potentially pathophysiological roles of SUMO proteases. These processes underpin normal brain function and their dysfunction is a key factor in age-related cognitive impairment and neurodegenerative diseases. Insight into brain function and dysfunction in aging and disease will provide economic, social and medical benefits. How might they benefit from this research? Our ultimate goal is that our discoveries will eventually translate into useful reagents that will facilitate healthier old age and increase the 'healthspan', thereby relieving pressure on health and welfare systems. This will directly benefit Pharma since it would provide new targets for conditions that currently do not have effective treatments. Another key goal is the effective and timely dissemination of knowledge to facilitate advances in the field. We have an excellent track record for freely distributing our knowledge, reagents and resources to other scientists. We frequently publish in highly regarded journals as soon as the data allows and we shall continue to participate in and help organize national and international conferences. We have an extensive and active network of local, national and international collaborators. In particular, our findings will inform the work of other labs at Bristol working on synaptic processes (e.g. J. Mellor, Z. Bashir, Mike Ashby, Graham Collingridge, R. Apps) and receptor and protein trafficking (e.g. J. Hanley, G. Banting, E. Molnar). We already enjoy added value from this critical mass of excellent neuroscientists at Bristol. We also have long-standing collaborations several big Pharma companies including Eli Lilly who supply us with transgenic animals and Ipsen, who currently fund a PhD student in our lab. Our other recent collaborators include UCB, Neurosearch and Lundbeck. We intend to maintain and expand such collaborations for mutually beneficial information exchange. The PI hosts Wellcome Trust, RCUK and charity funded post-docs and PhD students. Further, he regularly host overseas Masters students, all of whom benefit from the dynamic and active research environment.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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