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

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Epilepsy is a common disabling disorder characterized by seizures with complex genetic and environmental components. The absence of a definitive pathophysiology for epilepsy stymies the development of effective treatment strategies. In a small fraction of epilepsy cases however, single gene mutations may illuminate seizure-causing mechanisms, which may open the door to the discovery of broader, more effective therapeutic strategies. We have previously shown that disruption of Prickle genes in multiple species including humans, results in a predisposition to seizures. Those findings support Prickle in a seizure-preventing role and presents a possible anti-seizure therapeutic target. We identified the deubiquitinase Usp9x (ubiquitin-specific peptidase 9 X-linked) as a new Prickle binding partner which stabilized Prickle by preventing its degradation. In mice lacking the Usp9x protein in their forebrains, Prickle2 was barely detectable. In seizure-prone prickle mutant Drosophila, reducing fat facets (Drosophila usp9x) genetically or by a small-molecule usp9x inhibitor (Degrasyn/WP1130) suppressed the seizures. We also found 2 epilepsy patients harboring mutations in USP9X. Our findings demonstrate that inhibition of Usp9x can arrest prickle-mediated seizures, and variations in USP9X may predispose to seizures. From these studies, we have elucidated a seizure-inducing mechanism, identified a potential anti-seizure target, and a potential anti-seizure drug.

Vyšlo v časopise: Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005022
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005022

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