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Paemka, L., Mahajan, V.B., Ehaideb, S.N., Skeie, J.M., Tan, M.C., Wu, S., Cox, A.J., Sowers, L.P., Gecz, J., Jolly, L., Ferguson, P.J., Darbro, B., Schneider, A., Scheffer, I.E., Carvill, G.L., Mefford, H.C., El-Shanti, H., Wood, S.A., Manak, J.R., Bassuk, A.G. (2015). Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.  PLoS Genet. 11(3): e1005022.
FlyBase ID
FBrf0230423
Publication Type
Research paper
Abstract

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.

PubMed ID
PubMed Central ID
PMC4357451 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    PLoS Genet.
    Title
    PLoS Genetics
    Publication Year
    2005-
    ISBN/ISSN
    1553-7404 1553-7390
    Data From Reference
    Alleles (4)
    Genes (2)
    Human Disease Models (1)