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

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    39
    Author
    Paemka, L; Mahajan, VB; Ehaideb, SN; Skeie, JM; Tan, MC; Wu, S; Cox, AJ; Sowers, LP; Gecz, J; Jolly, L; ...
    Date
    2015-03-01
    Source Title
    PLoS Genetics
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Scheffer, Ingrid; Schneider, Amy
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    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 GENETICS, 11 (3), https://doi.org/10.1371/journal.pgen.1005022.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/260096
    DOI
    10.1371/journal.pgen.1005022
    NHMRC Grant code
    NHMRC/628952
    NHMRC/628952
    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.

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