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

doi:10.1016/j.celrep.2023.112004

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

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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 and J Robert Manak

Cell reports (Cambridge), Vol.42(1), 112004

01/14/2023

DOI: 10.1016/j.celrep.2023.112004

PMCID: PMC9942582

PMID: 36641750

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Abstract

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.

Epilepsy

Oxidative Stress

CP: Immunology

prickle

neuronal cell death

innate immunity

CP: Neuroscience

neurodegeneration

seizure disorder

glia

Details

Title: Subtitle: Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model
Creators: Krishna M Nukala - University of Iowa
Anthony J Lilienthal - University of Iowa
Shu Hui Lye - University of Alabama
Alexander G Bassuk - Roy J. and Lucille A. Carver College of Medicine
Stanislava Chtarbanova - University of Alabama
J Robert Manak - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.42(1), 112004
DOI: 10.1016/j.celrep.2023.112004
PMID: 36641750
PMCID: PMC9942582
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Language: English
Date published: 01/14/2023
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center; Neurology (Pediatrics)
Record Identifier: 9984360035002771

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