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

• DOI: 10.1016/j.celrep.2023.112004
• Publication Date: 2023-01-14T16:53:44Z
• Authors: Krishna M. Nukala; Anthony J. Lilien...; Shu Hui Lye; Alexander G. Bassuk; Stanislava Chtarb...; J. Robert Manak
• Keywords: 0303 health sciences; Epilepsy; QH301-705.5; Down-Regulation; CP: Immunology; Article; Immunity, Innate; 3. Good health; Oxidative Stress; 03 medical and health sciences; Drosophila melanogaster; Seizures; CP: Neuroscience; Animals; Humans; Drosophila; Biology (General); Neuroglia

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 suppresses 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.