Aagab-driven SHIP2 degradation rescues mitochondrial dysfunction in hypoxic-ischemic encephalopathy

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe brain disorder caused by oxygen deprivation.
• Mitochondrial oxidative stress and neuronal injury are key pathological mechanisms in HIE.
• The Aagab-NEDD4-1-SHIP2 pathway regulates neuronal function via protein ubiquitination and degradation.

Purpose of the Study:

• To investigate the role of the Aagab-NEDD4-1-SHIP2 axis in HIE pathogenesis.
• To determine the impact of this axis on mitochondrial oxidative stress in HIE.
• To explore the therapeutic potential of targeting this pathway for HIE treatment.

Main Methods:

• Multi-omics analysis of HIE and control rat brain datasets.
• In vitro studies using oxygen-glucose deprivation (OGD) neuronal models.
• In vivo experiments involving lentiviral gene silencing in neonatal rat HIE models.
• Mechanistic assays to elucidate protein interactions and degradation pathways.

Main Results:

• SHIP2 was significantly upregulated in HIE tissues and linked to oxidative stress.
• SHIP2 knockdown in vitro improved neuronal viability and reduced oxidative stress markers.
• Silencing SHIP2 in vivo ameliorated neurological deficits and reduced brain lesions in HIE rats.
• Aagab overexpression promoted NEDD4-1-mediated SHIP2 ubiquitination and degradation.

Conclusions:

• The Aagab-NEDD4-1-SHIP2 axis plays a critical role in HIE by modulating mitochondrial oxidative stress.
• Aagab facilitates NEDD4-1-mediated degradation of SHIP2, alleviating neuronal injury.
• Targeting the Aagab-NEDD4-1-SHIP2 pathway offers a potential therapeutic strategy for HIE.