Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X),a De-Ubiquitinase

Epilepsy is a common disabling disease with complex,multifactorial genetic and environmental etiology. the small fraction of epilepsies subject to mendelian inheritance offers key insight into epilepsy disease mechanisms; and pathologies brought on by mutations in a single gene can point the way to generalizable therapeutic strategies. mutations in the prickle genes can cause seizures in humans,zebrafish,mice,and flies,suggesting the seizure-suppression pathway is evolutionarily conserved. this pathway has never been targeted for novel anti-seizure treatments. here,the mammalian prickle-interactome was defined,identifying prickle-interacting proteins that localize to synapses and a novel interacting partner,usp9x,a substrate-specific de-ubiquitinase. prickle and usp9x interact through their carboxy-termini; and usp9x de-ubiquitinates prickle,protecting it from proteasomal degradation. in forebrain neurons of mice,usp9x deficiency reduced levels of prickle2 protein. genetic analysis suggests the same pathway regulates prickle-mediated seizures. the seizure phenotype was suppressed in prickle mutant flies by the small-molecule usp9x inhibitor,degrasyn/wp1130,or by reducing the dose of fat facets a usp9x orthologue. usp9x mutations were identified by resequencing a cohort of patients with epileptic encephalopathy,one patient harbored a de novo missense mutation and another a novel coding mutation. both usp9x variants were outside the prickle-interacting domain. these findings demonstrate that usp9x inhibition can suppress prickle-mediated seizure activity,and that usp9x variants may predispose to seizures. these studies point to a new target for anti-seizure therapy and illustrate the translational power of studying diseases in species across the evolutionary spectrum. © 2015 paemka et al.