Mechanisms and consequences of synaptic SUMOylation in health and disease

Project Information

SUMOBRAIN

Grant agreement ID: 232881

Closed project

Start date 1 May 2009

End date 30 April 2015

Funded under

• Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Total cost € 2 148 871,00

EU contribution € 2 148 871,00

Coordinated by

UNIVERSITY OF BRISTOL
United Kingdom

Final Report Summary - SUMOBRAIN (Mechanisms and consequences of synaptic SUMOylation in health and disease)

SUMOBrain has been a highly successful project. Our results have made major contributions in the field and have opened unanticipated new avenues of investigation. The aims of the project were:

1) Identification and functional characterisation of synaptic SUMO substrates.
2) SUMO regulation of presynaptic neurotransmitter release.
3) Activity-dependence of SUMO and SENP trafficking to synapses.
4) Role of SUMOylation in regulating protein – protein interactions at synapses:
5) Roles of synaptic protein SUMOylation in ischaemia.

We achieved significant progress in each of these aims and, in consequence, we have gained important insights into the regulation, roles and consequences of neuronal SUMOylation. Our discoveries increased understanding of how dysfunctional SUMOylation is implicated in clinically important neurological and neurodegenerative diseases and raised the possibility of identifying novel targets for therapeutic drug design.

Major highlights include:

1) We discovered that phosphorylation of the GluK2 subunit of kainate receptors by protein kinase PKC leads directly to GluK2 SUMOylation. This increased SUMOylation signals GluK2 endocytosis. Thus, direct phosphorylation by PKC and GluK2 SUMOylation are intimately linked to regulate the surface expression, function and plasticity of GluK2-containing KARs. This interplay between posttranslational modifications at GluK2 provides a highly flexible and sensitive control system that plays an important role in synaptic function and, equally importantly, serves as a template for investigating the regulation of other SUMO substrate proteins

2) We uncovered a new and unexpected cytoprotective pathway that leads to increased levels of SUMO-2/3-ylation in cells undergoing extreme stress. We showed that regulation of the stability of the deSUMOylating enzyme SENP3 is a critical factor in control SUMOylation of Drp1, a key regulator of mitochondrial fragmentation, cytochrome c release and apoptosis. We found that SUMOlation of Drp1 is neuroprotective because it hinders Drp1 recruitment for the cytosol to the mitochondrial outer membrane, thereby preventing fission and cytochrome c release.

3) We identified multiple presynaptic proteins that are SUMOylated and we have already published that the functions of RIM1α, synapsin and syntaxin are directly modulated by their SUMOylation status. Furthermore, we have elucidated the functional consequences on neurotransmitter release and synaptic function of their SUMOylation and deSUMOylation. For example, we showed that SUMOylation acts as a molecular switch to delineate the diverse functions of RIM1α, and represents a novel mechanism of presynaptic regulation of neurotransmission.

4) In addition to the knowledge generated, an important legacy of SUMOBrain is the library of new tools and reagents we have produced. These will underpin ongoing areas of investigation in our lab, and elsewhere, that we provide detailed molecular understanding of the causes, consequences and regulation of neuronal SUMOylation in health and disease.