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.
Subject(s)
JNK Mitogen-Activated Protein Kinases/metabolism , Membrane Proteins/metabolism , Neurons/physiology , Protein Processing, Post-Translational , Animals , Cell Survival , Cells, Cultured , Excitatory Amino Acid Agonists/metabolism , Hippocampus/pathology , Humans , Microarray Analysis , N-Methylaspartate/metabolism , Rats , UbiquitinationABSTRACT
Decades of research has shown that long-term changes in synaptic function ultimately require changes in gene expression.Recent work has focused on nuclear signaling by calcium and protein messengers initiated at postsynaptic sites. In this issue of The EMBO Journal, Ivanova and colleagues show that shuttling of CtBP-1 between presynaptic areas and nuclei regulates gene expression, which reminds us that presynaptic zones should not be ignored when considering synapse-to nucleus signaling.