Understanding the roles of SUMO proteases in neuronal function and viability
Award Number
BB/R00787X/1Status / Stage
ActiveDates
1 July 2018 -30 November 2023
Duration (calculated)
05 years 04 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£839,255.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of BristolContracted Centre Webpage
Principal Investigator
Professor Jeremy HenleyPI ORCID
0000-0003-3589-8335WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 371 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | BB/R00787X/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20180701 |
| End Date | 20231130 |
| Duration (calculated) | 05 years 04 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Bristol |
| Contracted Centre Webpage | |
| Funding Amount | £839,255.00 |
Abstract
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 In very recent, largely unpublished work, we show that the SUMO proteases SENP1 and SENP3 play defining roles in these processes.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.
Aims
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.