Journal article
Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase
PLoS genetics, Vol.11(3), pp.e1005022-e1005022
03/01/2015
DOI: 10.1371/journal.pgen.1005022
PMID: 25763846
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.
Details
- Title: Subtitle
- Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase
- Creators
- Lily Paemka - University of Iowa, SurgeryVinit B Mahajan - Stanford UniversitySalleh N Ehaideb - University of IowaJessica M Skeie - University of Iowa, Ophthalmology and Visual SciencesMen Chee Tan - Griffith UniversityShu Wu - University of Iowa, Internal MedicineAllison J Cox - University of Iowa, Stead Family Department of PediatricsLevi P Sowers - University of Iowa, Iowa Neuroscience InstituteJozef Gecz - School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, AustraliaLachlan Jolly - School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, AustraliaPolly J Ferguson - University of Iowa, Rheumatology, Allergy, and ImmunologyBenjamin Darbro - University of Iowa, Medical Genetics and GenomicsAmy Schneider - Epilepsy Research Centre, Department of Medicine, University of Melbourne, The Florey, Austin Health, Heidelberg, Melbourne, AustraliaIngrid E Scheffer - Austin HealthGemma L Carvill - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, United States of AmericaHeather C Mefford - Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, United States of AmericaHatem El-Shanti - University of Iowa, Medical Genetics and GenomicsStephen A Wood - Griffith UniversityJ Robert Manak - University of Iowa, BiologyAlexander G Bassuk - University of Iowa, Neurology (Pediatrics)
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.11(3), pp.e1005022-e1005022
- DOI
- 10.1371/journal.pgen.1005022
- PMID
- 25763846
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Grant note
- T32 GM008629 / NIGMS NIH HHS R21 MH100086 / NIMH NIH HHS R01 NS064159 / NINDS NIH HHS U54 HD083091 / NICHD NIH HHS R01 EY024665 / NEI NIH HHS K99 NS089858 / NINDS NIH HHS
- Language
- English
- Date published
- 03/01/2015
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Surgery; Biology; Craniofacial Anomalies Research Center; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics); Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9983992065502771
Metrics
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