ArticlePLoS genetics2015
Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 75 citations in OpenAlex.
- Potential Role of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) Abnormalities in Epileptogenesis: Multimodal Mechanisms and Therapeutic Targets.Molecular neurobiology · 2026Review
- DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46.Neurobiology of disease · 2025Article
- Evolving Insights into Prickle2 in Neurodevelopment and Neurological Disorders.Molecular neurobiology · 2025Review
- Downregulation of USP9X in the DG Region of the Hippocampus Leads to AD-Like Cognitive Dysfunction in Mice.CNS neuroscience & therapeutics · 2025Article
- Decoding Epilepsy: Prickle2 and Multifaceted Molecular Pathway Connections.Current pharmaceutical design · 2025Review
- The role of prickle proteins in vertebrate development and pathology.Molecular and cellular biochemistry · 2024Review
- Deubiquitinase BRCC3 promotes the migration, invasion and EMT progression of colon adenocarcinoma by stabilizing MET expression.Genes & genomics · 2024Article
- TBK1 Knockdown Alleviates Axonal Transport Deficits in Retinal Ganglion Cells Via mTORC1 Activation in a Retinal Damage Mouse Model.Investigative ophthalmology & visual science · 2023Article
- Novel Variant in theMolecular syndromology · 2023Article
- The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders.Biological psychiatry · 2022Review
- RANBP2 and USP9x regulate nuclear import of adenovirus minor coat protein IIIa.PLoS pathogens · 2022Article
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- Disorders of the eye, ear, skin, and nervous system in women with Turner syndrome -a nationwide cohort study.European journal of human genetics : EJHG · 2022Article
- USP30: Structure, Emerging Physiological Role, and Target Inhibition.Frontiers in pharmacology · 2022Review
- Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response.The Journal of biological chemistry · 2021Review
- USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bβ via deubiquitinating EGLN3.Journal of biomedical science · 2021Article
- The Ubiquitinated Axon: Local Control of Axon Development and Function by Ubiquitin.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Review
- The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development.Nature communications · 2021Article
- Deubiquitylating enzymes in neuronal health and disease.Cell death & disease · 2021Review
- Missense variant contribution to USP9X-female syndrome.NPJ genomic medicine · 2020Article
Corrections and comments
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Authors and funding
20 authors at 6 institutions in 3 countries.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.