Interaction of PRRT2 with Na+ channels: pathogenetic basis and new targets for the cure of PRRT2- associated paroxysmal disorders

Mutations in the PRRT2 gene that encodes for a neuron-specific membrane protein, are the cause of Infantile Benign Epilepsy, Kinesigenic Paroxysmal Dyskinesia, a movement disorder that occurs during adolescence, and more rarely of Hemiplegic Migraine or Episodic Ataxia. These diseases can be isolated or associate in the same patient. To date, over 1500 patients have been reported with 70 different PRRT2 mutations, 78% of which involve the insertion of an early stop signal in the PRRT2 gene. This causes insufficient levels of PRRT2 expression that becomes absent in the rare patients in which both PRRT2 genes are mutated. Our research group, thanks to previous Telethon funding, has uncovered that the lack of PRRT2 is associated with an increase in the activity of excitatory neurons in the Central Nervous System. This occurs because PRRT2 modulates the function of the sodium channels, fundamental proteins for the genesis and regulation of neuronal excitability. The new research aims at investigating the mechanisms and brain sites of neuronal hyperexcitability due to PRRT2 insufficiency that causes the variable paroxysmal pathologies. Our goal is to determine the molecular basis of the specific involvement of sodium channels, study the pathogenetic mechanisms underlying the severe involvement of the cerebellum and identify targeted therapies using advanced molecular and computational physiological approaches. The study of the relationships between PRRT2 and sodium channels will allow to identify new targeted therapies using specific channel blockers with fewer side effects that will optimize the treatment of these patients.