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Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. | LitMetric

AI Article Synopsis

  • Elevated c-Jun levels are linked to neurodegenerative diseases and can lead to neuronal cell death after brain injuries like strokes and seizures.
  • The study reveals that the protein Proline rich 7 (PRR7) accumulates in neurons after NMDAR activation and enhances the activity of c-Jun, contributing to cell death.
  • PRR7's role in inhibiting c-Jun's degradation suggests it connects NMDAR activity to c-Jun functioning, providing a new understanding of how excitotoxicity occurs in neurons.

Article Abstract

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 SCF(FBW) (7) (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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007554PMC
http://dx.doi.org/10.15252/embj.201593070DOI Listing

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