Connecting oxidative stress and brain immune system activation with epilepsy progression

September 6, 2023 @ 04:00 pm to 05:00 pm

John Manak, University of Iowa

108 Wartik Laboratory
University Park

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 brain 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 (Imd or Toll pathways) leads to a reduction in neuronal death, which in turn suppresses seizure activity, with oxidative stress acting upstream of IIR. These data provide the first direct genetic evidence that oxidative stress in combination with glial-mediated IIR leads to progression of an epilepsy disorder.

About the Speaker:

Upon obtaining his PhD studying oncogenes with Dr. Ron Prywes (Columbia University), Dr. Manak trained as a Drosophila molecular geneticist in the laboratories of Drs. Matthew Scott and Joe Lipsick (Stanford University). He began using flies to model human disorders in Dr. Lipsick’s laboratory, in particular studying the fly orthologue (Dm-Myb) of the c-Myb protooncogene (Nature, Nat Cell Biol, PNAS), and more recently (from work in his own laboratory) identifying a new function for Dm-Myb in stabilizing Polycomb repressive domains by contributing to topologically associating domain (TAD) function (Cell Reports). His laboratory also uses cutting-edge genomics techniques such as comparative genomic hybridization and whole exome sequencing to identify new genes/chromosomal microdeletions associated with a variety of genetic disorders, including spina bifida, bilateral renal agenesis, branchio-oto-renal syndrome, and cleft lip and/or palate (Hum Mol Genet, Genetics, Hum Genet, Am J Hum Genet). Dr. Manak also pioneered the use of microarrays to identify regions of unannotated transcription that led to identification of novel transcript isoforms which in turn allowed mapping of important gene mutations (Nature Genetics). Perhaps the most significant focus of his current laboratory has been to model an epilepsy syndrome in prickle mutant flies that is remarkably similar to what is observed in humans carrying PRICKLE mutations, including an early-onset, progressive epilepsy featuring myoclonic and tonic-clonic seizures as well as ataxia (PNAS, Am J Hum Genet, PLoS Genet, Ann Clin Transl Neurol). Additionally, the Manak lab has used this model to focus on the intersections between oxidative stress, the innate immune system, and epilepsy (Cell Reports). Details of this work will be the subject of his seminar.

Contact

Santhosh Girirajan
sxg47@psu.edu