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

TY - JOUR

T1 - Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity

AU - Kravchick, Dana O

AU - Karpova, Anna

AU - Hrdinka, Matous

AU - Lopez-Rojas, Jeffrey

AU - Iacobas, Sanda

AU - Carbonell, Abigail U

AU - Iacobas, Dumitru A

AU - Kreutz, Michael R

AU - Jordan, Bryen A

N1 - © 2016 The Authors.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.15252/embj.201593070

DO - 10.15252/embj.201593070

M3 - SCORING: Journal article

C2 - 27458189

VL - 35

SP - 1923

EP - 1934

JO - EMBO J

JF - EMBO J

SN - 0261-4189

IS - 17

ER -