title: Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity.
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.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Dana O
authors.initials: DO
authors.lastname: Kravchick
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Karpova
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Matous
authors.initials: M
authors.lastname: Hrdinka
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lopez-Rojas
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Iacobas
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Abigail U
authors.initials: AU
authors.lastname: Carbonell
authors.affiliation: Department of Pathology, New York Medical College, Valhalla, NY, USA.
authors.forename: Dumitru A
authors.initials: DA
authors.lastname: Iacobas
authors.affiliation: 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.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
authors.affiliation: 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.
authors.forename: Bryen A
authors.identifier: 0000-0002-4967-444X
authors.initials: BA
authors.lastname: Jordan
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D046228:Microarray Analysis; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D054875:Ubiquitination
chemical_list: D018690:Excitatory Amino Acid Agonists; D008565:Membrane Proteins; C000620902:PRR7 protein, human; D016202:N-Methylaspartate; D048031:JNK Mitogen-Activated Protein Kinases
keywords: FBW7; immediate early gene; ischemia; photoactivation; synapse to nucleus