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Dihydropyrimidinase-Related Protein 2 Is a New Partner in the Binding between 4E-BP2 and eIF4E Related to Neuronal
Emma Martínez-Alonso1,2, Alejandro Escobar-Peso1, Natalia Guerra-Pérez3
1Department of Research, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain.
Abstract:
Transient cerebral ischemia induces neuronal degeneration, followed in time by secondary delayed neuronal death that is strongly correlated with a permanent inhibition of protein synthesis in vulnerable brain regions, while protein translational rates are recovered in resistant areas. In the translation-regulation initiation step, the eukaryotic initiation factor (eIF) 4E is a key player regulated by its association with eIF4E-binding proteins (4E-BPs), mostly 4E-BP2 in brain tissue. In a previous work, we identified dihydropyrimidinase-related protein 2 (DRP2) as a 4E-BP2-interacting protein. Here, using a proteomic approach in a model of transient cerebral ischemia, a detailed study of DRP2 was performed in order to address the challenge of translation restoration in vulnerable regions. In this report, several DRP2 isoforms that have a specific interaction with both 4E-BP2 and eIF4E were identified, showing significant and opposite differences in this association, and being differentially detected in resistant and vulnerable regions in response to ischemia reperfusion. Our results provide the first evidence of DRP2 isoforms as potential regulators of the 4E-BP2-eIF4E association that would have consequences in the delayed neuronal death under ischemic-reperfusion stress. The new knowledge reported here identifies DRP2 as a new target to promote neuronal survival after cerebral ischemia.
Insights
Dihydropyrimidinase-related protein 2 (DRP2) isoforms regulate protein synthesis after brain ischemia. These DRP2 isoforms offer a new therapeutic target for promoting neuronal survival following ischemic-reperfusion injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Transient cerebral ischemia causes delayed neuronal death linked to inhibited protein synthesis in vulnerable brain regions.
- Protein synthesis regulation involves eukaryotic initiation factor 4E (eIF4E) and its binding proteins, particularly 4E-binding protein 2 (4E-BP2) in the brain.
- Previous research identified dihydropyrimidinase-related protein 2 (DRP2) as a 4E-BP2 interacting protein.
Purpose of the Study:
- To investigate the role of DRP2 isoforms in regulating protein synthesis following transient cerebral ischemia.
- To explore DRP2's interaction with 4E-BP2 and eIF4E in the context of ischemic-reperfusion stress.
- To identify DRP2 as a potential therapeutic target for enhancing neuronal survival after stroke.
Main Methods:
- Proteomic analysis in a transient cerebral ischemia model.
- Identification and characterization of DRP2 isoforms.
- Assessment of DRP2, 4E-BP2, and eIF4E interactions.
- Differential detection of DRP2 in resistant and vulnerable brain regions post-ischemia.
Main Results:
- Several DRP2 isoforms with specific interactions with 4E-BP2 and eIF4E were identified.
- These DRP2 isoforms exhibited significant and opposing differences in their association patterns.
- DRP2 isoforms were differentially detected in brain regions resistant versus vulnerable to ischemia-reperfusion.
- This suggests DRP2 isoforms modulate the 4E-BP2-eIF4E complex.
Conclusions:
- DRP2 isoforms are identified as novel regulators of the 4E-BP2-eIF4E association.
- These findings provide insights into the mechanisms of delayed neuronal death following cerebral ischemia.
- DRP2 represents a promising new therapeutic target for promoting neuronal survival in stroke patients.
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