| http://purl.uniprot.org/citations/28212375 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/28212375 | http://www.w3.org/2000/01/rdf-schema#comment | "The neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2, is an epilepsy-associated gene with at least three missense mutations identified in epileptic patients. Nedd4-2 encodes a ubiquitin E3 ligase that has high affinity toward binding and ubiquitinating membrane proteins. It is currently unknown how Nedd4-2 mediates neuronal circuit activity and how its dysfunction leads to seizures or epilepsies. In this study, we provide evidence to show that Nedd4-2 mediates neuronal activity and seizure susceptibility through ubiquitination of GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, (AMPAR). Using a mouse model, termed Nedd4-2andi, in which one of the major forms of Nedd4-2 in the brain is selectively deficient, we found that the spontaneous neuronal activity in Nedd4-2andi cortical neuron cultures, measured by a multiunit extracellular electrophysiology system, was basally elevated, less responsive to AMPAR activation, and much more sensitive to AMPAR blockade when compared with wild-type cultures. When performing kainic acid-induced seizures in vivo, we showed that elevated seizure susceptibility in Nedd4-2andi mice was normalized when GluA1 is genetically reduced. Furthermore, when studying epilepsy-associated missense mutations of Nedd4-2, we found that all three mutations disrupt the ubiquitination of GluA1 and fail to reduce surface GluA1 and spontaneous neuronal activity when compared with wild-type Nedd4-2. Collectively, our data suggest that impaired GluA1 ubiquitination contributes to Nedd4-2-dependent neuronal hyperactivity and seizures. Our findings provide critical information to the future development of therapeutic strategies for patients who carry mutations of Nedd4-2."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.org/dc/terms/identifier | "doi:10.1371/journal.pgen.1006634"xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Lee K.Y."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Zhu J."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Chung H.J."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Tsai N.P."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Man H.Y."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/author | "Jewett K.A."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/date | "2017"xsd:gYear |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/name | "PLoS Genet"xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/pages | "e1006634"xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/title | "Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors."xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://purl.uniprot.org/core/volume | "13"xsd:string |
| http://purl.uniprot.org/citations/28212375 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/28212375 |
| http://purl.uniprot.org/citations/28212375 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/28212375 |
| http://purl.uniprot.org/uniprot/#_A0A494B953-mappedCitation-28212375 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/28212375 |
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