2. Academic Validation
  3. Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity

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

  • EMBO J. 2016 Sep 1;35(17):1923-34. doi: 10.15252/embj.201593070.
Dana O Kravchick 1,  Anna Karpova 2,  Matous Hrdinka 2,  Jeffrey Lopez-Rojas 2,  Sanda Iacobas 3,  Abigail U Carbonell 1,  Dumitru A Iacobas 3,  Michael R Kreutz 4,  Bryen A Jordan 5
Affiliations

Affiliations

  • 1 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 2 Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
  • 3 Department of Pathology, New York Medical College, Valhalla, NY, USA.
  • 4 Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany Leibniz Group "Dendritic Organelles and Synaptic Function", Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 5 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA bryen.jordan@einstein.yu.edu.
PMID: 27458189 DOI: 10.15252/embj.201593070
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.

Keywords

FBW7; immediate early gene; ischemia; photoactivation; synapse to nucleus.

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