Epilepsja związana z białkami PRICKLE u owadów — defekt neurorównowagi powstający w mózgu

Damaging DNA variants in genes cause epilepsy from flies to humans. While classic work, primarily in flies, has demonstrated that PRICKLE proteins work with other planar cell polarity proteins to polarize epithelial sheets, the function of PRICKLE proteins in the nervous system is still unclear and may play distinct roles in the nervous system of different organisms. We thus sought to compare and contrast with genes in vertebrate systems in order to identify unifying roles across species. First, we find that similar to expression of the mouse , fly is expressed in a wide variety of CNS neurons, in particular post-mitotic maturing neuroblasts and neurons. However, unlike in the mouse, fly is not enriched in the axon initial segment (AIS) but is broadly distributed across the entire length of the expressing neurons. Second, we find that targeted expression of the  () isoform in a) glutamatergic neurons or b) a region analogous to the human brain stem in mutant animals suppresses seizures, implicating dysfunction of these neurons in seizure progression. Strikingly, targeting expression to only larval/pupal stages can fully rescue adult seizures, demonstrating that this form of epilepsy can be considered a neurodevelopmental defect such that an abnormality that occurs during development leads to a disorder that is late-onset. Finally, targeting expression exclusively in mutant brains suppresses seizures, demonstrating that, similar to humans, -associated epilepsy arises in the brain. Consistent with this result, removal of the head of mutants also significantly reduces seizures, confirming that brain neuronal dysfunction contributes to fly seizures.