Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase

PLoS Genetics
Lily PaemkaAlexander G Bassuk

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. U...Continue Reading

References

Sep 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·O Siddiqi, S Benzer
Jul 1, 1977·The Journal of General Virology·F L GrahamR Nairn
May 1, 1971·Proceedings of the National Academy of Sciences of the United States of America·D T SuzukiR Williamson
Aug 29, 1998·The Journal of Cell Biology·S TayaK Kaibuchi
Sep 6, 2001·Journal of Neurophysiology·D KueblerM A Tanouye
Dec 4, 2003·Molecular and Cellular Biology·Masahito Shimojo, Louis B Hersh
Dec 6, 2003·Proceedings of the National Academy of Sciences of the United States of America·Hong ChenPietro V De Camilli
Mar 19, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Pedro Gonzalez-Alegre, Henry L Paulson
Nov 4, 2008·American Journal of Human Genetics·Alexander G BassukHatem I El-Shanti
Jan 30, 2009·Molecular Biology of the Cell·Lachlan A JollyStephen A Wood
Apr 21, 2009·Nature Genetics·Patrick S TarpeyMichael R Stratton
Apr 22, 2009·Cell·Masahiro NarimatsuJeffrey L Wrana
Dec 22, 2009·Nature·Martin SchwickartVishva M Dixit
Nov 1, 2011·Molecular and Cellular Biology·Avais M DaulatStéphane Angers
May 1, 2012·Neuron·Ivan IossifovMichael Wigler
Oct 5, 2012·The New England Journal of Medicine·Joep de LigtLisenka E L M Vissers
Jan 30, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lindsey N MicelGail S Eckhardt
Mar 13, 2014·American Journal of Human Genetics·Claire C HomanLachlan A Jolly
Jul 16, 2014·Proceedings of the National Academy of Sciences of the United States of America·Salleh N EhaidebJ Robert Manak
Sep 30, 2014·American Journal of Human Genetics·UNKNOWN EuroEPINOMICS-RES ConsortiumUNKNOWN Epi4K Consortium

❮ Previous
Next ❯

Citations

Sep 30, 2015·Lancet Neurology·UNKNOWN EpiPM Consortium
Apr 12, 2017·Neurochemical Research·James P ReynoldsDavid C Henshall
Apr 1, 2017·Nature Communications·Xin LiLei Shi
Jan 14, 2017·Neuroscience Letters·Simona Balestrini, Sanjay M Sisodiya
Oct 23, 2018·American Journal of Medical Genetics. Part a·Mario MastrangeloVincenzo Leuzzi
Jan 15, 2020·ELife·Bomsoo ChoJeffrey D Axelrod
Sep 21, 2016·Annals of Clinical and Translational Neurology·Salleh N EhaidebJ Robert Manak
Dec 20, 2018·Neurogenetics·Yukiko HataNaoki Nishida
Apr 12, 2019·British Journal of Cancer·Avais M DaulatFrançois Bertucci
May 28, 2019·Frontiers in Physiology·Nagore EluUgo Mayor
Jul 30, 2017·Scientific Reports·Alessandra GaspariniEmanuela Leonardi
Jun 18, 2017·The Journal of Biological Chemistry·Qian WangWenshu Ge
Oct 3, 2017·BMC Medical Genetics·Gudny A ArnadottirKari Stefansson
Jan 16, 2016·PLoS Genetics·Arunesh Saras, Mark A Tanouye
Jan 24, 2021·Cell Death & Disease·Fatima Amer-SarsourAvraham Ashkenazi
Nov 15, 2020·Cerebral Cortex·Maria A KashermanMichael Piper
Dec 11, 2020·NPJ Genomic Medicine·Lachlan A JollyJozef Gecz
Mar 27, 2021·Nature Communications·Trisha A Macrae, Miguel Ramalho-Santos
Aug 16, 2021·The Journal of Biological Chemistry·Nathan A Snyder, Gustavo M Silva

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Methods Mentioned

BETA
ubiquitination
co-IPs
deubiquitination
fluorescence microscopy
electrophoresis
X-ray
PCR

Software Mentioned

Polyphen
PRICKLE
MASCOT
Cytoscape
Scaffold
SpectrumMill
EVS

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