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.
| Original language | English |
|---|---|
| Article number | e1005022 |
| Journal | PLoS Genetics |
| Volume | 11 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 12 Mar 2015 |
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ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Ecology, Evolution, Behavior and Systematics
- Cancer Research
- Genetics(clinical)
Cite this
Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase. / 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; Schneider, Amy; Scheffer, Ingrid E.; Carvill, Gemma L.; Mefford, Heather C.; El-Shanti, Hatem; Wood, Stephen A.; Manak, J. Robert; Bassuk, Alexander G.
In: PLoS Genetics, Vol. 11, No. 3, e1005022, 12.03.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase
AU - Paemka, Lily
AU - Mahajan, Vinit B.
AU - Ehaideb, Salleh N.
AU - Skeie, Jessica M.
AU - Tan, Men Chee
AU - Wu, Shu
AU - Cox, Allison J.
AU - Sowers, Levi P.
AU - Gecz, Jozef
AU - Jolly, Lachlan
AU - Ferguson, Polly J.
AU - Darbro, Benjamin
AU - Schneider, Amy
AU - Scheffer, Ingrid E.
AU - Carvill, Gemma L.
AU - Mefford, Heather C.
AU - El-Shanti, Hatem
AU - Wood, Stephen A.
AU - Manak, J. Robert
AU - Bassuk, Alexander G.
PY - 2015/3/12
Y1 - 2015/3/12
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1005022
DO - 10.1371/journal.pgen.1005022
M3 - Article
VL - 11
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 3
M1 - e1005022
ER -