Investigating the genetics of seizure-prone flies

Researchers have identified the basic cellular mechanism that causes epilepsy-like seizures in prickle mutant flies (Drosophila melanogaster). The study identifies a novel pathway in the pathophysiology of epilepsy.

In multiple species, including flies, mice, zebrafish and humans, mutations in orthologs of the prickle gene result in epileptic phenotypes. Seizure-prone prickle mutant flies show behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) that are similar to other fly models of seizure disorders. Little is known about the cellular process that leads to these phenotypes, however.

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J. Robert Manak (University of Iowa, Iowa City) led a study to answer this question. To determine whether mutations in prickle were solely responsible for the seizure phenotype in flies, Manak's team studied flies in which the balance between two isoforms of the prickle gene in neurons was altered: one group was partly deficient in the pk^sple isoform, and one group was partly deficient in the pk^pk isoform. After subjecting the flies to a behavioral assay in which they were mechanically stimulated with a vortex mixer for 20 s, they assessed the flies' recovery time. Flies in which the pk^pk isoform predominated had longer recovery times, and they also showed increased susceptibility to seizures induced by electroconvulsive stimulation (Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1403357111; published online 14 July 2014).

Products of prickle work in conjunction with a group of cytoplasmic and membrane-associated proteins that must be properly transported within vesicles in order for normal communication between neurons to occur. To determine how prickle isoforms may modify the transport of these important proteins to cause seizures, the researchers assessed the movement of vesicles along axons in D. melanogaster larvae. Both groups of flies with altered levels of prickle isoforms showed impaired vesicle transport, demonstrating that the balance between prickle isoforms is important for normal vesicle transport in axons of fly neurons. Overall, when the balance was tipped towards pk^pk isoforms, anterograde vesicle movement was enhanced, altering axon polarity and leading to seizures. Consistent with this finding, seizures were suppressed when vesicle transport was impeded by reducing expression of two motor proteins responsible for the movement of vesicles along axons.

Interestingly, the pathway implicated in underlying seizures in this study has previously been associated with neurodegenerative diseases. The study may lead to further associations between the cellular dynamics underlying epilepsy and those underlying neurodegenerative disorders such as Alzheimer's disease.