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 SCFFBW 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1923-1934 |
| Number of pages | 12 |
| Journal | EMBO Journal |
| Volume | 35 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2016 |
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Keywords
- FBW7
- immediate early gene
- ischemia
- photoactivation
- synapse to nucleus
ASJC Scopus subject areas
- Neuroscience(all)
- Medicine(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
Cite this
Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. / Kravchick, Dana O.; Karpova, Anna; Hrdinka, Matous; Lopez-Rojas, Jeffrey; Iacobas, Sanda; Carbonell, Abigail U.; Iacobas, Dumitru A.; Kreutz, Michael R.; Jordan, Bryen A.
In: EMBO Journal, Vol. 35, No. 17, 01.09.2016, p. 1923-1934.Research output: Contribution to journal › Article
}
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.
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 SCFFBW 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 SCFFBW 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 - FBW7
KW - immediate early gene
KW - ischemia
KW - photoactivation
KW - synapse to nucleus
UR - http://www.scopus.com/inward/record.url?scp=84984868340&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984868340&partnerID=8YFLogxK
U2 - 10.15252/embj.201593070
DO - 10.15252/embj.201593070
M3 - Article
C2 - 27458189
AN - SCOPUS:84984868340
VL - 35
SP - 1923
EP - 1934
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 17
ER -