Epilepsy gene prickle ensures neuropil glial ensheathment through regulating cell adhesion molecules

Human PRICKLE1 gene has been associated with epilepsy. However, the under-lying pathogenetic mechanisms remain elusive. Here we report a Drosophila prickle mutant pk(IG1-1) exhibiting strong epileptic seizures and, intriguingly, abnormal glial wrapping. We found that pk is required in both neurons and glia, particularly neuropil ensheathing glia (EGN), the fly analog of oligodendrocyte, for protecting the animal from seizures. We further revealed that Pk directly binds to the membrane skeleton binding protein Ankyrin 2 (Ank2), thereby regulating the cell adhesion molecule Neuroglian (Nrg). Such protein interactions also apply to their human homologues. Moreover, nrg and ank2 mutant flies also display seizure phenotypes, and expression of either Nrg or Ank2 rescues the seizures of pk(IG1-1) flies. Therefore, our findings indicate that Prickle ensures neuron-glial interaction within neuropils through regulating cell adhesion between neurons and ensheathing glia. Dysregulation of this process may represent a conserved pathogenic mechanism underlying PRICKLE1-associated epilepsy.

Automated summary

The mutation of the Drosophila prickle gene causes epileptic seizures and abnormal glial wrapping in insects, suggesting a crucial role of this gene in both neurons and glia. It regulates cell adhesion between neurons and ensheathing glia, ensuring neuron-glial interaction within neuropils. Dysregulation of this process may contribute to PRICKLE1-associated epilepsy.