Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/97196
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Type: Journal article
Title: Seizures are regulated by ubiquitin-specific peptidase 9 x-linked (USP9X), a de-ubiquitinase
Author: Paemka, L.
Mahajan, V.
Ehaideb, S.
Skeie, J.
Tan, M.
Wu, S.
Cox, A.
Sowers, L.
Gecz, J.
Jolly, L.
Ferguson, P.
Darbro, B.
Schneider, A.
Scheffer, I.
Carvill, G.
Mefford, H.
El-Shanti, H.
Wood, S.
Manak, J.
Bassuk, A.
Citation: PLoS Genetics, 2015; 11(3):e1005022-1-e1005022-16
Publisher: Public Library of Science
Issue Date: 2015
ISSN: 1553-7404
1553-7404
Statement of
Responsibility: 
Lily Paemka, Vinit B. Mahajan, Salleh N. Ehaideb, Jessica M. Skeie, Men Chee Tan, Shu Wu, Allison J. Cox, Levi P. Sowers, Jozef Gecz, Lachlan Jolly, Polly J. Ferguson, Benjamin Darbro, Amy Schneider, Ingrid E. Scheffer, Gemma L. Carvill, Heather C. Mefford, Hatem El-Shanti, Stephen A. Wood, J. Robert Manak, Alexander G. Bassuk
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.
Keywords: Animals; Humans; Mice; Drosophila melanogaster; Seizures; Ubiquitin Thiolesterase; Mass Spectrometry
Rights: © 2015 Paemka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
RMID: 0030024233
DOI: 10.1371/journal.pgen.1005022
Grant ID: http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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