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 (PRR7) accumulates in the nucleus of hippocampal neurons following NMDAR activity. We find that PRR7 inhibits the ubiquitination of c‐Jun by E3 ligase SCFFBW7 (FBW7), increases c‐Jun‐dependent transcriptional activity, and promotes neuronal death. Microarray assays show that PRR7 abundance is directly correlated with transcripts associated with cellular viability. Moreover, PRR7 knockdown attenuates NMDAR‐mediated excitotoxicity in neuronal cultures in a c‐Jun‐dependent manner. Our results show that PRR7 links NMDAR activity to c‐Jun function and provide new insights into the molecular processes that underlie NMDAR‐dependent excitotoxicity.
The transcription factor c‐Jun regulates NMDA receptor‐dependent neuronal death. Proline rich 7 (PRR7) is a synaptic protein that shuttles to the nucleus upon NMDA receptor stimulation, upregulates c‐Jun abundance by inhibiting its ubiquitination, and plays a role in neuronal excitotoxicity.
PRR7 binds to NMDA receptors and is a novel activity‐dependent synaptonuclear messenger in hippocampal neurons.
PRR7 inhibits the ubiquitination of c‐Jun by the SCF‐complex E3 ligase, FBW7.
PRR7 nuclear transport elevates c‐Jun abundance, increases c‐Jun transcriptional activity, and promotes neuronal death.
PRR7 activity regulates transcripts associated with cellular viability, and loss of PRR7 is neuroprotective.
- Received September 14, 2015.
- Revision received June 17, 2016.
- Accepted June 21, 2016.
- © 2016 The Authors