PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity

Fruscione, Floriana; Valente, Pierluigi; Sterlini, Bruno; Romei, Alessandra; Baldassari, Sımona; Fadda, Manuela; Prestigio, Cosimo; Giansante, Giorgia; Sartorelli, Jacopo; Rossi, P; Rubio, Alicia; Gambardella, Antonio; Nieus, Thierry; Broccoli, Vania; Fassio, Anna; Baldelli, Pietro; Corradi, Anna; Zara, Federico; Benfenati, Fabio

doi:10.1093/brain/awy051

Cited by 113 publications

(137 citation statements)

References 51 publications

(80 reference statements)

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“…16 Given that attacks of PKD are suppressed by carbamazepine, the molecular mechanism of the attacks could involve transient hyperactivity of VGSCs due to the activity-dependent cleavage of PRRT2. 16 Given that attacks of PKD are suppressed by carbamazepine, the molecular mechanism of the attacks could involve transient hyperactivity of VGSCs due to the activity-dependent cleavage of PRRT2.…”

Section: Significance Of the Cleavage Of Prrt2 To 12k-ctfmentioning

confidence: 99%

“…Third, the cleavage might enhance the VGSC activities at the AIS, followed by greater action potentials through the transient retraction of the PRRT2 function negatively modulating Na V 1.2/1.6, subunits of VGSCs. 16 Given that attacks of PKD are suppressed by carbamazepine, the molecular mechanism of the attacks could involve transient hyperactivity of VGSCs due to the activity-dependent cleavage of PRRT2. Taken together, the three putative mechanisms mediated by the cleavage of PRRT2 might result in transient dysfunctions of PRRT2 and an activity-dependent enhancement of neuronal excitation.…”

Section: Significance Of the Cleavage Of Prrt2 To 12k-ctfmentioning

confidence: 99%

“…13 In addition, PRRT2 is reported to interact with GluR1, a subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor (AMPAR), 14,15 and to downregulate the surface expression of GluR1. 16 PRRT2 is widely expressed in the central nervous system 17 and its functions have been analyzed in various brain regions, including cerebral cortex, [18][19][20] hippocampus, 21 and cerebellum. 16 PRRT2 is widely expressed in the central nervous system 17 and its functions have been analyzed in various brain regions, including cerebral cortex, [18][19][20] hippocampus, 21 and cerebellum.…”

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confidence: 99%

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

et al. 2019

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Mutations of PRRT2 (proline‐rich transmembrane protein 2) cause several neurological disorders, represented by paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements triggered by sudden voluntary movements. PRRT2 is reported to suppress neuronal excitation, but it is unclear how the function of PRRT2 is modulated during neuronal excitation. We found that PRRT2 is processed to a 12 kDa carboxy‐terminal fragment (12K‐CTF) by calpain, a calcium‐activated cysteine protease, in a neuronal activity‐dependent manner, predominantly via NMDA receptors or voltage‐gated calcium channels. Furthermore, we clarified that 12K‐CTF is generated by sequential cleavages at Q220 and S244. The amino‐terminal fragment (NTF) of PRRT2, which corresponds to PKD‐related truncated mutants, is not detected, probably due to rapid cleavage at multiple positions. Given that 12K‐CTF lacks most of the proline‐rich domain, this cleavage might be involved in the activity‐dependent enhancement of neuronal excitation perhaps through transient retraction of PRRT2's function. Therefore, PRRT2 might serve as a buffer for neuronal excitation, and lack of this function in PKD patients might cause neuronal hyperexcitability in their motor circuits.

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Section: Significance Of the Cleavage Of Prrt2 To 12k-ctfmentioning

confidence: 99%

Section: Significance Of the Cleavage Of Prrt2 To 12k-ctfmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2019

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“…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 . A study in homozygous patient‐derived induced pluripotent stem cells revealed that PRRT2 also directly binds and negatively regulates voltage‐gated Na + channels Na v 1.2 and Na v 1.6, resulting in increased Na + currents in homozygous cells . In vitro knockdown in primary neurons results in synaptic defects; namely decreased synaptic contacts, reduced synchronous neurotransmitter release and an insensitivity to extracellular Ca 2+ .…”

Section: Introductionmentioning

confidence: 99%

“…13,17,18 A study in homozygous patient-derived induced pluripotent stem cells revealed that PRRT2 also directly binds and negatively regulates voltage-gated Na + channels Na v 1.2 and Na v 1.6, resulting in increased Na + currents in homozygous cells. 19 In vitro knockdown in primary neurons results in synaptic defects; namely decreased synaptic contacts, reduced synchronous neurotransmitter release and an insensitivity to extracellular Ca 2+ . 18 A role for PRRT2 in inhibition of vesicle fusion at the synapse has also been described.…”

Section: Introductionmentioning

confidence: 99%

Paroxysmal and cognitive phenotypes in Prrt2 mutant mice

Robertson

Featherby

Howell

et al. 2019

Genes Brain and Behavior

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Mutations in proline‐rich transmembrane protein 2 (PRRT2) cause a range of episodic disorders that include paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy. Mutations are generally loss of function and include the c649dupC frameshifting mutation that is present in around 80% of affected individuals. To investigate how Prrt2 loss of function mutations causes disease, we performed a phenotypic investigation of a transgenic Prrt2 knockout (Prrt2 KO) mouse. We observed spontaneous paroxysmal episodes with behavioural features of both seizure and movement disorders, as well as unexplained deaths in KO and HET animals. KO mice showed spatial learning deficits in the Morris water maze, as well as gait abnormalities in the quantitative Digigait analysis; both of which may be representative of the more severe phenotypes experienced by homozygous patients. These findings extend the described phenotypes of Prrt2 mutant mice, further confirming their utility for in vivo investigation of the role of Prrt2 mutations in episodic diseases.

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PRRT2‐positive self‐limited infantile epilepsy: Initial seizure characteristics and response to sodium channel blockers

et al. 2023

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Objective Self‐limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2‐positive SeLIE only, and anti‐seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2‐positive SeLIE and to propose effective anti‐seizure medications for seizure control. Methods We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal‐onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2‐related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti‐seizure medications. Results Patients with PRRT2‐related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short‐duration (n = 33, 91.7%), and bilateral tonic–clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One‐third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti‐seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. Significance Our results delineated the clinical characteristics of PRRT2‐positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti‐seizure medications for initial clustered seizure control. If afebrile bilateral tonic–clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2‐positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.

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PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity

Cited by 113 publications

References 51 publications

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

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

Paroxysmal and cognitive phenotypes in Prrt2 mutant mice

PRRT2‐positive self‐limited infantile epilepsy: Initial seizure characteristics and response to sodium channel blockers

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