Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723000153 |
| _version_ | 1797952150158966784 |
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| author | Krishna M. Nukala Anthony J. Lilienthal Shu Hui Lye Alexander G. Bassuk Stanislava Chtarbanova J. Robert Manak |
| author_facet | Krishna M. Nukala Anthony J. Lilienthal Shu Hui Lye Alexander G. Bassuk Stanislava Chtarbanova J. Robert Manak |
| author_sort | Krishna M. Nukala |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T22:42:42Z |
| format | Article |
| id | doaj.art-7b3d4ce31289455297677276d5dc0cb7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T22:42:42Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7b3d4ce31289455297677276d5dc0cb72023-01-16T04:07:53ZengElsevierCell Reports2211-12472023-01-01421112004Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy modelKrishna M. Nukala0Anthony J. Lilienthal1Shu Hui Lye2Alexander G. Bassuk3Stanislava Chtarbanova4J. Robert Manak5Department of Biology, University of Iowa, Iowa City, IA 52242, USADepartment of Biology, University of Iowa, Iowa City, IA 52242, USADepartment of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USADepartment 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, USADepartment of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723000153CP: NeuroscienceCP: Immunology |
| spellingShingle | Krishna M. Nukala Anthony J. Lilienthal Shu Hui Lye Alexander G. Bassuk Stanislava Chtarbanova J. Robert Manak Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model Cell Reports CP: Neuroscience CP: Immunology |
| title | Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| title_full | Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| title_fullStr | Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| title_full_unstemmed | Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| title_short | Downregulation of oxidative stress-mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| title_sort | downregulation of oxidative stress mediated glial innate immune response suppresses seizures in a fly epilepsy model |
| topic | CP: Neuroscience CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723000153 |
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