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PRR7 is a novel NMDA-dependent inhibitor of c-Jun ubiquitination in neurons

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 such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE62686 | GEO | 2014/10/25

SECONDARY ACCESSION(S): PRJNA264800

REPOSITORIES: GEO

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PRR7 is a novel NMDA-dependent inhibitor of c-Jun ubiquitination in neurons

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