This study investigates the role of PA2G4/EBP1 ubiquitination by PRKN/PARKIN in promoting mitophagy to protect neurons from death following cerebral ischemia-reperfusion injury. The research demonstrates that PA2G4/EBP1 levels increase early during transient middle cerebral artery occlusion, preventing neuronal death by inducing mitophagy. Neuron-specific Knockout of Pa2g4 resulted in increased infarct volume and aggravated neuron loss with impaired mitophagy, which was rescued by introducing adeno-associated virus serotype 2 expressing PA2G4/EBP1. The study further reveals that PA2G4/EBP1 is ubiquitinated on lysine 376 by PRKN/PARKIN on damaged mitochondria and interacts with receptor protein SQSTM1/p62 for mitophagy induction.
Neuron-specific Knockout of Pa2g4 increased infarct volume and aggravated neuron loss with impaired mitophagy. Introduction of PA2G4/EBP1 via adeno-associated virus serotype 2 rescued these effects, highlighting the neuroprotective role of PA2G4/EBP1-mediated mitophagy in cerebral ischemia.
The study utilized a neuron-specific Pa2g4 conditional Knockout mouse model to assess the effects of PA2G4/EBP1 deficiency on neuronal survival and mitophagy following cerebral ischemia-reperfusion injury.
Cerebral ischemia, Neuronal death, Mitophagy, Ubiquitination, Neuroprotection
Conditional Knockout mouse model, Neuron-specific gene deletion, Mitophagy assessment, Ubiquitination analysis, IRES, reporter
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