Journal article
prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies
Proceedings of the National Academy of Sciences - PNAS, Vol.111(30), pp.11187-11192
07/29/2014
DOI: 10.1073/pnas.1403357111
PMCID: PMC4121842
PMID: 25024231
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.
Details
- Title: Subtitle
- prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies
- Creators
- Salleh N Ehaideb - Interdisciplinary Graduate Programs in Genetics,King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh 11426, Kingdom of Saudi ArabiaAtulya Iyengar - Neuroscience, andAtsushi Ueda - Departments of Biology andGary J Iacobucci - Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260Cathryn Cranston - Molecular and Cellular Biology andAlexander G Bassuk - Pediatrics, University of Iowa, Iowa City, IA 52242David Gubb - Reponse Immunitaire et Developpment, Centre National de la Recherche Scientifique, 67084 Strasbourg Cedex, France; andJeffrey D Axelrod - Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305Shermali Gunawardena - Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260Chun-Fang Wu - Interdisciplinary Graduate Programs in Genetics,Neuroscience, andDepartments of Biology andJ Robert Manak - Interdisciplinary Graduate Programs in Genetics,Departments of Biology andPediatrics, University of Iowa, Iowa City, IA 52242; john-manak@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(30), pp.11187-11192
- DOI
- 10.1073/pnas.1403357111
- PMID
- 25024231
- PMCID
- PMC4121842
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- United States
- Grant note
- F31 NS082001 / NINDS NIH HHS P50 GM107615 / NIGMS NIH HHS R37 GM059823 / NIGMS NIH HHS NS 082001 / NINDS NIH HHS GM 088804 / NIGMS NIH HHS R01 GM088804 / NIGMS NIH HHS R01 GM097081 / NIGMS NIH HHS
- Language
- English
- Date published
- 07/29/2014
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center; Neurology (Pediatrics); Ophthalmology and Visual Sciences
- Record Identifier
- 9983991999302771
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