title: The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy.
abstract: 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 α-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.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Kong
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Gan
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China. Electronic address: yf3079@foxmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
mesh_terms: D000249:Adenosine Monophosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D007976:Leupeptins / Q000627:therapeutic use; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity; D000075702:Nedd4 Ubiquitin Protein Ligases; D009474:Neurons / Q000187:drug effects; D010862:Pilocarpine / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000494:pharmacology
chemical_list: D018692:Antimanic Agents; D015853:Cysteine Proteinase Inhibitors; D056827:Endosomal Sorting Complexes Required for Transport; D007976:Leupeptins; D018721:Muscarinic Agonists; D034741:RNA, Small Interfering; D025801:Ubiquitin; D014452:Ubiquitins; C039343:ubiquitin adenylate; D010862:Pilocarpine; D000249:Adenosine Monophosphate; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases; D018021:Lithium Chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Mesial temporal lobe epilepsy; Nedd4-2; Ubiquitin; Ubiquitin–proteasome system