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

Lily Paemka, Vinit B. Mahajan, Salleh N. Ehaideb, Jessica M. Skeie, Men Chee Tan, Shu Wu, Allison J. Cox, Levi P. Sowers, Jozef Gecz, Lachlan Jolly, Polly J. Ferguson, Benjamin Darbro, Amy Schneider, Ingrid E. Scheffer, Gemma L. Carvill, Heather C. Mefford, Hatem El-Shanti, Stephen A. Wood, J. Robert Manak, Alexander G. Bassuk

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 languageEnglish
Article numbere1005022
JournalPLoS Genetics
Volume11
Issue number3
DOIs
Publication statusPublished - 12 Mar 2015

Fingerprint

peptidases
seizures
ubiquitin
Ubiquitin
Seizures
Peptide Hydrolases
mutation
plant spines
epilepsy
Epilepsy
Mutation
Diptera
protein
ubiquitin isopeptidase
seizure
gene
etiology
genetic analysis
pathology
Mendelian inheritance

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Paemka, L., Mahajan, V. B., Ehaideb, S. N., Skeie, J. M., Tan, M. C., Wu, S., ... Bassuk, A. G. (2015). Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase. PLoS Genetics, 11(3), [e1005022]. https://doi.org/10.1371/journal.pgen.1005022

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 journalArticle

Paemka, L, Mahajan, VB, Ehaideb, SN, Skeie, JM, Tan, MC, Wu, S, Cox, AJ, Sowers, LP, Gecz, J, Jolly, L, Ferguson, PJ, Darbro, B, Schneider, A, Scheffer, IE, Carvill, GL, Mefford, HC, El-Shanti, H, Wood, SA, Manak, JR & Bassuk, AG 2015, 'Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase', PLoS Genetics, vol. 11, no. 3, e1005022. https://doi.org/10.1371/journal.pgen.1005022
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. / Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase. In: PLoS Genetics. 2015 ; Vol. 11, No. 3.
@article{5f7c8598ec0942ab91fc96a867e3875b,
title = "Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase",
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.",
author = "Lily Paemka and Mahajan, {Vinit B.} and Ehaideb, {Salleh N.} and Skeie, {Jessica M.} and Tan, {Men Chee} and Shu Wu and Cox, {Allison J.} and Sowers, {Levi P.} and Jozef Gecz and Lachlan Jolly and Ferguson, {Polly J.} and Benjamin Darbro and Amy Schneider and Scheffer, {Ingrid E.} and Carvill, {Gemma L.} and Mefford, {Heather C.} and Hatem El-Shanti and Wood, {Stephen A.} and Manak, {J. Robert} and Bassuk, {Alexander G.}",
year = "2015",
month = "3",
day = "12",
doi = "10.1371/journal.pgen.1005022",
language = "English",
volume = "11",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "3",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84926227698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926227698&partnerID=8YFLogxK

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 -