Abstract
SummaryMutations 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.
Highlights
An array of mutations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) are linked to a wide group of paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizures, infantile convulsions with choreoathetosis, and episodic ataxia (Gardiner et al, 2015)
We report that the N-terminal proline-rich region on PRRT2 selectively blocks synaptic SNARE-mediated fusion by preventing the initial engagement of the SNARE proteins and modulates the vesicle priming process
PRRT2 Inhibits Synaptic SNARE-Mediated Fusion of Liposomes Informed by the recent findings that PRRT2 may interact with the core synaptic fusion machinery (Lee et al, 2012; Tan et al, 2017; Valente et al, 2016), we used a defined fusion system (Weber et al, 1998) to identify the molecular role of PRRT2 at the synapse
Summary
An array of mutations (e.g., non-sense, frameshift, missense) in the gene encoding proline-rich transmembrane protein 2 (PRRT2) are linked to a wide group of paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizures, infantile convulsions with choreoathetosis, and episodic ataxia (Gardiner et al, 2015). Biallelic (homozygous and compound heterozygous) mutations in PRRT2 have been reported in a small number of PKD patients, typically associated with a more severe movement disorder phenotype, learning difficulties, and only partial response to carbamazepine (Delcourt et al, 2015; Gardiner et al, 2015). PRRT2 knockout (KO) and loss-of-function mutant mice display pleiotropic paroxysmal phenotypes and faithfully recapitulate the neurological diseases associated with PRRT2 mutations (Michetti et al, 2017; Tan et al, 2017). These results indicate that pathogenicity of PRRT2 mutations is likely due to loss of function and a dominant-negative effect
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
