title: prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies.
abstract: Recent analyses in flies, mice, zebrafish, and humans showed that mutations in prickle orthologs result in epileptic phenotypes, although the mechanism responsible for generating the seizures was unknown. Here, we show that Prickle organizes microtubule polarity and affects their growth dynamics in axons of Drosophila neurons, which in turn influences both anterograde and retrograde vesicle transport. We also show that enhancement of the anterograde transport mechanism is the cause of the seizure phenotype in flies, which can be suppressed by reducing the level of either of two Kinesin motor proteins responsible for anterograde vesicle transport. Additionally, we show that seizure-prone prickle mutant flies have electrophysiological defects similar to other fly mutants used to study seizures, and that merely altering the balance of the two adult prickle isoforms in neurons can predispose flies to seizures. These data reveal a previously unidentified pathway in the pathophysiology of seizure disorders and provide evidence for a more generalized cellular mechanism whereby Prickle mediates polarity by influencing microtubule-mediated transport.
authors.affiliation: Interdisciplinary Graduate Programs in Genetics,King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh 11426, Kingdom of Saudi Arabia;
authors.forename: Salleh N
authors.initials: SN
authors.lastname: Ehaideb
authors.affiliation: Neuroscience, and.
authors.forename: Atulya
authors.initials: A
authors.lastname: Iyengar
authors.affiliation: Departments of Biology and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ueda
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260;
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Iacobucci
authors.affiliation: Molecular and Cellular Biology and.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Cranston
authors.affiliation: Pediatrics, University of Iowa, Iowa City, IA 52242;
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.affiliation: Reponse Immunitaire et Developpment, Centre National de la Recherche Scientifique, 67084 Strasbourg Cedex, France; and.
authors.forename: David
authors.initials: D
authors.lastname: Gubb
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Axelrod
authors.affiliation: Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260;
authors.forename: Shermali
authors.initials: S
authors.lastname: Gunawardena
authors.affiliation: Interdisciplinary Graduate Programs in Genetics,Neuroscience, andDepartments of Biology and.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Wu
authors.affiliation: Interdisciplinary Graduate Programs in Genetics,Departments of Biology andPediatrics, University of Iowa, Iowa City, IA 52242; john-manak@uiowa.edu.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D060588:LIM Domain Proteins; D020033:Protein Isoforms; C121600:pk protein, Drosophila
keywords: EB1-GFP; epilepsy; neurodegeneration; planar cell polarity; spiny-legs