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

Dana O. Kravchick, Anna Karpova, Matous Hrdinka, Jeffrey Lopez-Rojas, Sanda Iacobas, Abigail U. Carbonell, Dumitru A. Iacobas, Michael R. Kreutz, Bryen A. Jordan

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10 Scopus citations

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 SCFFBW 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.

Original languageEnglish (US)
Pages (from-to)1923-1934
Number of pages12
JournalEMBO Journal
Volume35
Issue number17
DOIs
StatePublished - Sep 1 2016

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Keywords

  • FBW7
  • immediate early gene
  • ischemia
  • photoactivation
  • synapse to nucleus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Kravchick, D. O., Karpova, A., Hrdinka, M., Lopez-Rojas, J., Iacobas, S., Carbonell, A. U., Iacobas, D. A., Kreutz, M. R., & Jordan, B. A. (2016). Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. EMBO Journal, 35(17), 1923-1934. https://doi.org/10.15252/embj.201593070