Journal
JOURNAL OF CELL BIOLOGY
Volume 201, Issue 5, Pages 725-740Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201206063
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Funding
- Deutsche Forschungsgemeinschaft [SFB/TR3, SFB645]
- Bundesministeriums fur Bildung und Forschung (Nationale Genomforschungsnetz-Netzwerk Epilepsie und Migr ne and Unabh ngige Forschergruppen in den Neurowissenschaften)
- Fernandez-Busnadiego is recipient of a Feodor-Lynen
- Alexander von Humboldt Foundation
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Synaptic vesicles are embedded in a complex filamentous network at the presynaptic terminal. Before fusion, vesicles are linked to the active zone (AZ) by short filaments (tethers). The identity of the molecules that form and regulate tethers remains unknown, but Rab3-interacting molecule (RIM) is a prominent candidate, given its central role in AZ organization. In this paper, we analyzed presynaptic architecture of RIM1. knockout (KO) mice by cryo-electron tomography. In stark contrast to previous work on dehydrated, chemically fixed samples, our data show significant alterations in vesicle distribution and AZ tethering that could provide a structural basis for the functional deficits of RIM1. KO synapses. Proteasome inhibition reversed these structural defects, suggesting a functional recovery confirmed by electrophysiological recordings. Altogether, our results not only point to the ubiquitin-proteasome system as an important regulator of presynaptic architecture and function but also show that the tethering machinery plays a critical role in exocytosis, converging into a structural model of synaptic vesicle priming by RIM1..
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