Increased oxidative stress precedes activation of the seizure-exacerbating glial immune response in prickle mutants
Authors: Krishna Madhav Nukala 1; Anthony Lilienthal 1; Shu Hui Lye 2; Alexander Bassuk 3; Stanislava Chtarbanova 2; J. Robert Manak 1,3
Affiliations: 1) Department of Biology, University of Iowa, Iowa City, IA; 2) Department of Biological Sciences, University of Alabama, Tuscaloosa, AL; 3) Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA
Keywords: e. epilepsy; g. oxidative damage
Epilepsy is a neurological disorder characterized by seizures and affects ~1% of the U.S. population. We have previously shown that mutations in prickle (pk) cause spontaneous myoclonic-like seizures and ataxia in Drosophila, similar to what is observed in humans carrying PRICKLE mutations. Moreover, a transcriptome analysis of pk mutant brains revealed a robust increase in glial-mediated innate innate immune response (GIIR), suggesting that the immune response might be connnected to seizure progression. Using genetic, behavioral and immunohistochemical methods, we also showed that inhibiting the GIIR leads to a reduction of neurodegeneration which in turn suppresses the age-related exacerbation of seizures in pk mutants. However, while these experiments were the first to genetically demonstrate a link between a brain-derived innate immune system activation and epilepsy exacerbation, the link between pk neuronal dysfunction and activation of the GIIR remained unclear. Several studies have linked increased oxidative stress to numerous neurological disease models including epilepsy, and we observe significant upregulation of antioxidant genes in our transcriptome data, suggesting that oxidative stress might be the initiating factor for GIIR and eventual seizure exacerbation. Here, we show that larval, but not adult, pk mutant brains show increased neuronal oxidative stress, while only adult pk mutant brains show a significant increase in antioxidant and innate immune responses. Together, these data show that oxidative stress precedes the activation of GIIR and may be responsible for generating the signal to the glia, thus identifying a potential mechanism for GIIR-associated seizure generation in pk mutants.This work is supported by NIH/NINDS R01NS098590.