Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model

Previous work in our laboratory has shown that mutations in prickle (pk) cause myoclonic-like seizures and ataxia in Drosophila, similar to what is observed in humans carrying mutations in orthologous PRICKLE genes. Here, we show that pk mutant brains show elevated, sustained neuronal cell death that correlates with increasing seizure penetrance, as well as an upregulation of mitochondrial oxidative stress and innate immune response (IIR) genes. Moreover, flies exhibiting more robust seizures show increased levels of IIR-associated target gene expression suggesting they may be linked. Genetic knockdown in glia of either arm of the IIR (Immune Deficiency [Imd] or Toll) leads to a reduction in neuronal death, which in turn sup-presses seizure activity, with oxidative stress acting upstream of IIR. These data provide direct genetic evidence that oxidative stress in combination with glial-mediated IIR leads to progression of an epilepsy disorder.

Automated summary

Previous work has shown that mutations in prickle cause seizures and ataxia in Drosophila, similar to human mutations in orthologous PRICKLE genes. The study reveals that pk mutant brains exhibit elevated neuronal cell death, mitochondrial oxidative stress, and innate immune response gene upregulation, which correlate with increased seizure activity. Knockdown of the immune deficiency or Toll pathways in glia reduces neuronal death and suppresses seizure activity, indicating that oxidative stress acts upstream of the innate immune response in the progression of epilepsy.