USP11-PGAM5 Axis Promotes Neurotoxic Astrocyte Reactivity by Aggravating the mtDNA-cGAS-STING Pathway After...

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Astrocyte transformation into a neurotoxic phenotype exacerbates secondary brain injury following intracerebral hemorrhage (ICH).
• Understanding the mechanisms regulating neurotoxic astrocyte reactivity is crucial for developing effective ICH treatments.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying neurotoxic astrocyte reactivity in ICH.
• To identify novel therapeutic targets for mitigating brain injury after ICH.

Main Methods:

• Analysis of perihematomal tissue from ICH patients and mice.
• Identification of USP11 as a deubiquitinase for PGAM5.
• Genetic knockout studies (Usp11, Pgam5) in astrocytes.
• Investigation of mitochondrial pathways (mPTP, Drp1, mtDNA leakage) and the cGAS-STING pathway.
• Development of angiopep-2 modified extracellular vesicles for targeted siRNA delivery.

Main Results:

• Neurotoxic astrocyte reactivity correlates with phosphoglycerate mutase family member 5 (PGAM5) expression.
• USP11 deubiquitinates PGAM5, preventing its degradation and increasing its levels in neurotoxic astrocytes.
• Knockout of Usp11 or Pgam5 in astrocytes reduces neurotoxicity, neuronal apoptosis, and improves neurofunctional recovery.
• PGAM5 promotes mitochondrial dysfunction and mtDNA leakage, activating the cGAS-STING pathway.
• Targeting mtDNA or the cGAS-STING pathway attenuates USP11-PGAM5-driven astrocyte reactivity.
• Targeted delivery of Pgam5 siRNA via extracellular vesicles improved neurological function in ICH models.

Conclusions:

• The USP11-PGAM5 axis is a key driver of neurotoxic astrocyte reactivity in ICH through regulation of the mtDNA-cGAS-STING pathway.
• USP11 and PGAM5 represent potential therapeutic targets for treating ICH.
• Targeted delivery systems, like angiopep-2 modified EVs, show promise for treating ICH.