PRRT2 Is a Key Component of the Ca 2+ -Dependent Neurotransmitter Release Machinery

Abstract

SummaryHeterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.

SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

“…However, a study demonstrated a presynaptic role for Prrt2 in regulated exocytosis of neurotransmitter via interaction with synaptotagmin (Valente et al, 2016). Presynaptic release failure is a valid concern in the interpretation of tetanic stimulation-induced LTP for SynDIG4 −/− mice discussed earlier.…”

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

“…A second protein of relevance in the context of Munc13-1 function and dyskinesia is PRRT2, a synaptic proline-rich transmembrane protein that binds the SNARE protein SNAP25 (17,76) and synaptotagmin 1 and synaptotagmin 2 (77). PRRT2 variants are linked to paroxysmal kinesigenic dyskinesia with infantile epilepsy (PKD/IC) (17) and fever-related infantile seizures (78).…”

“…PRRT2 variants are linked to paroxysmal kinesigenic dyskinesia with infantile epilepsy (PKD/IC) (17) and fever-related infantile seizures (78). Reduced PRRT2 levels cause a complex phenotype, including a reduction in synapse numbers, a parallel increase in SV numbers and in the RRP size at the remaining synapses, reductions in the frequency and amplitude of spontaneous synaptic events, and reduced APevoked EPSCs (77). These findings indicate that PRRT2 is involved in the control of p r , and it was suggested that it functionally links the SNARE complex and synaptotagmins to increase the Ca 2+ sensitivity of the SV fusion machinery.…”

Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy

“…Seizure disorders associated with many of these newly identified mutations manifest in early childhood and are accompanied by serious behavioral comorbidities: SYN1 (Giannandrea et al, 2013; Paemka et al, 2013), STXBP1 (Stamberger et al, 2016), Prrt2 (Liu et al, 2016; Valente et al, 2016), NAPB (Conroy et al, 2016), SV2a. (Serajee and Huq, 2015).…”