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

Dana O. Kravchick; Anna Karpova; Matous Hrdinka; Jeffrey Lopez-Rojas; Sanda Iacobas; Abigail U. Carbonell; Dumitru A. Iacobas; Michael R. Kreutz; Bryen A. Jordan

doi:10.15252/embj.201593070

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

Dana O. Kravchick, Anna Karpova, Matous Hrdinka, Jeffrey Lopez-Rojas, Sanda Iacobas, Abigail U. Carbonell, Dumitru A. Iacobas, Michael R. Kreutz, Bryen A. Jordan

Neuroscience

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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^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.

Original language	English (US)
Pages (from-to)	1923-1934
Number of pages	12
Journal	EMBO Journal
Volume	35
Issue number	17
DOIs	https://doi.org/10.15252/embj.201593070
State	Published - Sep 1 2016

Keywords

FBW7
immediate early gene
ischemia
photoactivation
synapse to nucleus

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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@article{0588c19f36404bfdaecf441ff4a679c2,

title = "Synaptonuclear messenger PRR7 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 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.",

keywords = "FBW7, immediate early gene, ischemia, photoactivation, synapse to nucleus",

author = "Kravchick, {Dana O.} and Anna Karpova and Matous Hrdinka and Jeffrey Lopez-Rojas and Sanda Iacobas and Carbonell, {Abigail U.} and Iacobas, {Dumitru A.} and Kreutz, {Michael R.} and Jordan, {Bryen A.}",

note = "Funding Information: This work was supported by NIH grants AG039521 (B.A.J.), 5R01HL092001 (D.A.I.), SFB 779 TP B08 (M.R.K. and A.K.), SFB 854 TP7 and DFG Kr1879/5-1, 6-1 (M.R.K), and NIMH training fellowship 5F31MH095381 (D.O.K.). Flag-tagged FBW7 and rat GluA1 and GluA2-Myc constructs plasmids were kindly provided by Dr. Bruce Clurman and Dr. Martin Heine, respectively. AP-1 luciferase plasmid was generously provided by Dr. George Wilding. Rabbit PRR7 antibody was provided by Dr. Yoshinori Fujiyoshi. Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = sep,

day = "1",

doi = "10.15252/embj.201593070",

language = "English (US)",

volume = "35",

pages = "1923--1934",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Nature Publishing Group",

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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 - Funding Information: This work was supported by NIH grants AG039521 (B.A.J.), 5R01HL092001 (D.A.I.), SFB 779 TP B08 (M.R.K. and A.K.), SFB 854 TP7 and DFG Kr1879/5-1, 6-1 (M.R.K), and NIMH training fellowship 5F31MH095381 (D.O.K.). Flag-tagged FBW7 and rat GluA1 and GluA2-Myc constructs plasmids were kindly provided by Dr. Bruce Clurman and Dr. Martin Heine, respectively. AP-1 luciferase plasmid was generously provided by Dr. George Wilding. Rabbit PRR7 antibody was provided by Dr. Yoshinori Fujiyoshi. Publisher Copyright: © 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 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

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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 -

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

Abstract

Keywords

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