Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12680
Title: Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.
Authors: Paemka, Lily;Mahajan, Vinit B;Ehaideb, Salleh N;Skeie, Jessica M;Tan, Men Chee;Wu, Shu;Cox, Allison J;Sowers, Levi P;Gecz, Jozef;Jolly, Lachlan;Ferguson, Polly J;Darbro, Benjamin W;Schneider, Amy;Scheffer, Ingrid E;Carvill, Gemma L;Mefford, Heather C;El-Shanti, Hatem;Wood, Stephen A;Manak, J Robert;Bassuk, Alexander G
Affiliation: Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Program in Genetics, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America; Department of Biology, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Biology, The University of Iowa, Iowa City, Iowa, United States of America; King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, KSA.
Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States of America.
Interdisciplinary Graduate Program of Neuroscience, Department of Veterans Affairs Medical Center, Iowa City, Iowa, United States of America.
School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Program in Genetics, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America.
Epilepsy Research Centre, Department of Medicine, University of Melbourne, The Florey, Austin Health, Heidelberg, Melbourne, Australia.
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Qatar Biomedical Research Institute Medical Genetics Center, Doha, Qatar.
Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Program in Genetics, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America; Department of Biology, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Neuroscience, The University of Iowa, Iowa City, Iowa, United States of America.
Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Program in Genetics, The University of Iowa, Iowa City, Iowa, United States of America; Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Neuroscience, The University of Iowa, Iowa City, Iowa, United States of America.
Issue Date: 12-Mar-2015
Citation: Plos Genetics 2015; 11(3): e1005022
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.
Internal ID Number: 25763846
URI: http://ahro.austin.org.au/austinjspui/handle/1/12680
DOI: 10.1371/journal.pgen.1005022
URL: http://www.ncbi.nlm.nih.gov/pubmed/25763846
Type: Journal Article
Appears in Collections:Journal articles

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