4.5 Article

The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy

Journal

PHYSIOLOGY & BEHAVIOR
Volume 143, Issue -, Pages 104-112

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.physbeh.2015.02.026

Keywords

Mesial temporal lobe epilepsy; Ubiquitin-proteasome system; Ubiquitin; Nedd4-2

Funding

  1. Young Teachers of Central South University Booster Project [2011QNZT152]
  2. National Natural Science Foundation of China Youth Fund Project [81100846]

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Although the pathogenesis and epileptogenesis of mesial temporal lobe epilepsy (MTLE) have been studied for years, many questions remain. The ubiquitin-proteasome system (UPS) is one factor that might regulate ion channels, inflammation and neuron excitability. Nedd4-2 is an E3 ubiquitin ligase linked with ion channels and synaptic vesicle recycling. Here, we explore the role of the UPS and its E3 ligase Nedd4-2 in the pathogenesis of MTLE. Our western blot results revealed that ubiquitin and Nedd4-2 were expressed differentially in different stages of MTLE. Co-immunoprecipitation and double immunostaining results indicated that Nedd4-2 was the substrate protein of ubiquitin both in vivo and in vitro. Inhibition of the UPS aggravated the epileptogenesis of MTLE, causing early and frequent spontaneous seizures, more obvious neuron loss and aberrant mossy fiber sprouting. Inhibition of ubiquitin also enhanced the activation of Nedd4-2, and switched ion channel alpha-ENaC downstream. Our study is the first to report that the UPS participates in the pathogenesis of MTLE, inhibition of UPS could aggravate the epileptogenesis, and that Nedd4-2 is a critical E3 ligase involved in this process. (C) 2015 Elsevier Inc. All rights reserved.

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