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Synaptonuclear messenger PRR 7 inhibits c‐Jun ubiquitination and regulates NMDA ‐mediated excitotoxicity
Author(s) -
Kravchick Dana O,
Karpova Anna,
Hrdinka Matous,
LopezRojas Jeffrey,
Iacobas Sanda,
Carbonell Abigail U,
Iacobas Dumitru A,
Kreutz Michael R,
Jordan Bryen A
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593070
Subject(s) - neuroscience , excitotoxicity , library science , medicine , psychology , nmda receptor , computer science , receptor
Elevated c‐Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults including stroke and epilepsy. NMDA receptor ( NMDAR ) antagonists block c‐Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, the molecular mechanisms regulating c‐Jun abundance in neurons are poorly understood. Here, we show that the synaptic component Proline rich 7 ( PRR 7) accumulates in the nucleus of hippocampal neurons following NMDAR activity. We find that PRR 7 inhibits the ubiquitination of c‐Jun by E3 ligase SCF FBW 7 ( FBW 7), increases c‐Jun‐dependent transcriptional activity, and promotes neuronal death. Microarray assays show that PRR 7 abundance is directly correlated with transcripts associated with cellular viability. Moreover, PRR 7 knockdown attenuates NMDAR ‐mediated excitotoxicity in neuronal cultures in a c‐Jun‐dependent manner. Our results show that PRR 7 links NMDAR activity to c‐Jun function and provide new insights into the molecular processes that underlie NMDAR ‐dependent excitotoxicity.