Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model
Krishna M. Nukala,
Anthony J. Lilienthal,
Shu Hui Lye,
Alexander G. Bassuk,
Stanislava Chtarbanova,
J. Robert Manak
Affiliations
Krishna M. Nukala
Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Anthony J. Lilienthal
Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Shu Hui Lye
Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA
Alexander G. Bassuk
Department of Pediatrics, University of Iowa and Carver College of Medicine, Iowa City, IA 52242, USA; Department of Neurology, University of Iowa and Carver College of Medicine, Iowa City, IA 52242, USA; The Iowa Neuroscience Institute, University of Iowa and Carver College of Medicine, Iowa City, IA 52242, USA
Stanislava Chtarbanova
Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA
J. Robert Manak
Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Pediatrics, University of Iowa and Carver College of Medicine, Iowa City, IA 52242, USA; Corresponding author
Summary: 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.
