Role of Zfra in mitigating epileptic seizure due to WWOX downregulation

Abstract

As a tumor suppressor, WWOX is a recently defined risk factor for Alzheimer’s disease (AD). WWOX limits AD progression due, in part, to its suppression of tau tangle formation by direct binding of tau and tau‐phosphorylating enzymes. Deficiency of WWOX leads to severe neural diseases, including epileptic encephalopathy, microcephaly, intractable seizures and developmental delay, and early death in human and animal newborns. Wwox knockout mice, which survive in less than 1 month, display spontaneous and audiogenic seizures and rapid formation of tau and amyloid aggregates in the brain in less than 3 weeks after birth. During AD progression in humans and mice, pS14‐WWOX is shown to accumulate in the brain hippocampus and cortex. Suppression of pS14‐WWOX by a short synthetic peptide Zfra (zinc finger‐like protein that regulates apoptosis) leads to clear up of tau tangles and amyloid plaques, and restoration of memory loss in triple transgenic mice for AD. Here, we determined that when Wwox wild type and heterozygous mice were pre‐injected with a Zfra4–10 peptide via tail veins, these mice resisted pentylenetetrazone (PTZ)‐induced seizure. Mechanistically, Zfra significantly suppressed pS14‐WWOX in the auditory cortex and hippocampal CA1, CA3, or DG areas. Zfra blocked PTZ‐induced activation of inflammatory microglia and astrocytes in mouse hippocampus. Also, Zfra significantly blocked the expression of RE1‐silencing transcription factor (REST) (>90%), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Together, our observations suggest that Zfra peptide is a potent agent in mitigating epileptic seizure caused by WWOX deficiency.Support or Funding InformationMinistry of Science and Technology, Taiwan, National Health Research Institute, Taiwan, and Department of Defense, USA.