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PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly

Coleman, J; Jouannot, O; Ramakrishnan, SK; Zanetti, MN; Wang, J; Salpietro, V; Houlden, H; ... Krishnakumar, SS; + view all (2018) PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly. Cell Reports , 22 (3) pp. 820-831. 10.1016/j.celrep.2017.12.056. Green open access

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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.

Type: Article
Title: PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2017.12.056
Publisher version: http://doi.org/10.1016/j.celrep.2017.12.056
Language: English
Additional information: © 2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, PAROXYSMAL KINESIGENIC DYSKINESIA, MEMBRANE-FUSION, NEUROTRANSMITTER RELEASE, SYNAPTOTAGMIN-I, VESICLE FUSION, PROTEINS, EXOCYTOSIS, MUTATIONS, DYNAMICS, PROLINE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10043570
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