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

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Biology

Background:

• Elevated c-Jun levels are implicated in neuronal apoptosis and neurodegenerative diseases like Alzheimer's.
• NMDA receptor (NMDAR) antagonists protect neurons from excitotoxicity but the underlying mechanisms are unclear.
• The regulation of c-Jun abundance in neurons remains poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanisms linking NMDAR activity to c-Jun regulation and neuronal cell death.
• To investigate the role of the synaptic protein Proline Rich 7 (PRR7) in this pathway.

Main Methods:

• Investigated PRR7 localization and its interaction with c-Jun in hippocampal neurons.
• Utilized ubiquitination assays to study PRR7's effect on c-Jun degradation.
• Employed microarray analysis to assess PRR7's correlation with gene expression.
• Performed PRR7 knockdown experiments in neuronal cultures to evaluate its role in excitotoxicity.

Main Results:

• PRR7 accumulates in the nucleus of hippocampal neurons upon NMDAR activation.
• PRR7 inhibits the ubiquitination and degradation of c-Jun by the FBW7 E3 ligase.
• Increased PRR7 levels enhance c-Jun transcriptional activity and promote neuronal death.
• PRR7 knockdown significantly reduces NMDAR-mediated excitotoxicity in a c-Jun-dependent manner.

Conclusions:

• PRR7 acts as a crucial link between NMDAR activity and c-Jun-mediated neuronal apoptosis.
• PRR7's inhibition of c-Jun ubiquitination contributes to excitotoxicity.
• These findings offer new insights into the molecular basis of NMDAR-dependent neuronal cell death and potential therapeutic targets.