Synaptonuclear messenger PRR 7 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 FBW7 (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 NMDARmediated 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.

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

“…Differently labeled samples of biological replicates were hybridized over night with Agilent 60 mer 4x44k whole genome rat V2 arrays (#G2519F). Our optimized protocol [27] and the "multiple yellow" strategy [28] were used to profile each "condition"…”

Regulated transport of signaling proteins from synapse to nucleus

“…The authors then demonstrated that RNF10 translocates to the nucleus during LTP to regulate gene expression. Similarly, PRR7 was previously identified in the postsynaptic density, and then recently shown to translocate to the nucleus following NMDAR activation, where it enhances c-Jun-dependent transcriptional activity during excitotoxicity [18,21]. These studies used proteomic profiling of synapses in combination with predicted nuclear localization data to contribute to the growing body of work identifying the population of proteins that undergo activity-dependent translocation.…”

“…Several novel synaptonuclear signaling proteins have been identified by characterizing the proteome of excitatory synapses and the interactome of NMDA receptors [18-21]. These systematic approaches allow for the identification of proteins with putative nuclear localization signals (NLS) within the synapse.…”

Optic Nerve Crush Activates the Genomic Fabrics of the Complement Cascade and Delta-Notch Signaling

“…We applied an optimized protocol [47] for RNA extraction (Qiagen RNeasy mini-kit), reverse transcription (adding fluorescent tags) and hybridization onto Agilent G2519F 60mer two-colour gene expression rat 4×44k arrays in the "multiple yellow" design that provides maximum flexibility in comparing the conditions and 100% usage of the resources [48]. RNA concentrations before and after reverse transcription were estimated with a NanoDrop ND2000 Spectrophotometer, and purity was assessed with Agilent RNA 6000 Nano kit in an Agilent 2100 Bioanalyzer.…”