PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly.

Abstract

Mutations in proline-rich transmembrane protein 2 (PRRT2) are associated with a range of paroxysmal neurological disorders. PRRT2 predominantly localizes to the pre-synaptic terminals and is believed to regulate neurotransmitter release. However, the mechanism of action is unclear. Here, we use reconstituted single vesicle and bulk fusion assays, combined with live cell imaging of single exocytotic events in PC12 cells and biophysical analysis, to delineate the physiological role of PRRT2. We report that PRRT2 selectively blocks the trans SNARE complex assembly and thus negatively regulates synaptic vesicle priming. This inhibition is actualized via weak interactions of the N-terminal proline-rich domain with the synaptic SNARE proteins. Furthermore, we demonstrate that paroxysmal dyskinesia-associated mutations in PRRT2 disrupt this SNARE-modulatory function and with efficiencies corresponding to the severity of the disease phenotype. Our findings provide insights into the molecular mechanisms through which loss-of-function mutations in PRRT2 result in paroxysmal neurological disorders.

• Authors: Jeff Coleman, Ouardane Jouannot, Sathish K Ramakrishnan, Maria N Zanetti, Jing Wang, Vincenzo Salpietro, Henry Houlden, James E Rothman, Shyam S Krishnakumar
• Journal: Cell reports (Cell Rep) Vol. 22 Issue 3 Pg. 820-831 (01 16 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29346777 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Nerve Tissue Proteins
• PRRT2 protein, human
• SNARE Proteins

Topics

• Animals
• Humans
• Membrane Fusion
• Membrane Proteins (genetics, metabolism)
• Mutation
• Nerve Tissue Proteins (genetics, metabolism)
• PC12 Cells
• Presynaptic Terminals (metabolism)
• Rats
• SNARE Proteins (genetics, metabolism)
• Synaptic Transmission