PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum

Abstract

Mutations in the proline-rich transmembrane protein 2 (PRRT2) are associated with paroxysmal kinesigenic dyskinesia (PKD) and several other paroxysmal neurological diseases, but the PRRT2 function and pathogenic mechanisms remain largely obscure. Here we show that PRRT2 is a presynaptic protein that interacts with components of the SNARE complex and downregulates its formation. Loss-of-function mutant mice showed PKD-like phenotypes triggered by generalized seizures, hyperthermia, or optogenetic stimulation of the cerebellum. Mutant mice with specific PRRT2 deletion in cerebellar granule cells (GCs) recapitulate the behavioral phenotypes seen in Prrt2-null mice. Furthermore, recording made in cerebellar slices showed that optogenetic stimulation of GCs results in transient elevation followed by suppression of Purkinje cell firing. The anticonvulsant drug carbamazepine used in PKD treatment also relieved PKD-like behaviors in mutant mice. Together, our findings identify PRRT2 as a novel regulator of the SNARE complex and provide a circuit mechanism underlying the PRRT2-related behaviors.

Paroxysmal and cognitive phenotypes in Prrt2 mutant mice

“…PRRT2 spans 340 amino acids and contains two hydrophobic domains at the C‐terminus, resulting in a membrane‐bound protein of which the majority is intracellular . It is expressed throughout the brain, with strongest expression in the cerebellum, hippocampus and cortex . PRRT2 interacts with SNARE complex proteins SNAP‐25, STX1A and VAMP2, as well as Ca 2+ sensors Syt1/2, all of which are important regulators of synchronous neurotransmitter release at the pre‐synaptic terminal .…”

Activity‐dependent cleavage of dyskinesia‐related proline‐rich transmembrane protein 2 (PRRT2) by calpain in mouse primary cortical neurons

“…Actually, it is reported that PRRT2 suppresses exocytosis of synaptic vesicles 9 through interactions with SNARE proteins such as SNAP25, 10 syntaxin 1A/B, 11,12 VAMP2 13 and synaptotagmin 1/2. Actually, it is reported that PRRT2 suppresses exocytosis of synaptic vesicles 9 through interactions with SNARE proteins such as SNAP25, 10 syntaxin 1A/B, 11,12 VAMP2 13 and synaptotagmin 1/2.…”

“…15 Moreover, PRRT2 negatively modulates VGSCs by interacting with its subunits, Na V 1.2 and Na V 1.6. 11 However, it is not clearly understood which neural circuit is associated with the pathogenesis of PKD. 11 However, it is not clearly understood which neural circuit is associated with the pathogenesis of PKD.…”

PRRT2-dependent dyskinesia: cerebellar, paroxysmal and persistent

“…To unravel these mechanisms, Tan and colleagues generated several mouse models harboring global neuronal or region-specific PRRT2 truncations [2]. Mutant mice with global or cerebellum-specific truncation, but not forebrain-specific truncation, exhibited, similar to the clinical features of PKD in patients, severe episodes of aberrant motor behavior including dyskinesia and dystonic postures following generalized seizures and hyperthermia.…”

“…Question remains, which factors determine the duration of these episodes (often tens of minutes rather than seconds)? Does it merely depend on the initial event that evoked the abnormal firing pattern of Purkinje cells, which could include for example a period with seizures, stress or hyperthermia [2], or does it also depend on internal amplification mechanisms, such as those that are mediated by the projections from the cerebellar nuclei neurons to the granule cells in the cerebellar cortex [10] (Figure 1)? Given the similarities in duration of the behavioral and cerebellar neuronal correlates of the paroxysmal attacks in RODP mice [7,8] and that of the dysfunctional motor episodes in the murine models described in the paper by Tan and colleagues [2], it appears plausible that in both RODP and PKD prolonged interactive, yet erratic, firing patterns of Purkinje cells and their downstream targets in the nuclei underlie the pathological motor behavior.…”