Project Details
Projekt
Presynaptic tethers: molecular composition and functional role
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2015 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 280611691
Tethering synaptic vesicles to the presynaptic active zone plays a critical role in mediating the temporally and spatially tightly controlled release of neurotransmitter. Recently, we have shown that deletion of the core active zone protein RIM1a results in significant alterations in vesicle distribution and SV tethering at the active zone and that these structural as well as correlated functional deficits could be reversed by inhibition of the proteasome. Furthermore, our data indicate that the number and length of tethers are indicative of the vesicle progression towards release. We propose to use the combination of cryo-electron microscopy, a method that allows three-dimensional imaging of fully hydrated synapses at a single nanometer resolution, with electrophysiological and biochemical approaches to advance our understanding of the molecular nature of the structures involved in regulating presynaptic release. Specifically, we will investigate the roles of some specific proteins in synaptic vesicle tethering and the molecular basis of the observed structural heterogeneity of presynaptic terminals in RIM1a KO mice. Furthermore, we propose to identify proteins responsible for the proteasome inhibitor induced recovery of the presynaptic release in RIM1a KO synapses and thereby expand our understanding of the molecular mechanisms of the regulation of presynaptic release by ubiquitin-proteasome system.
DFG Programme
Research Grants
