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CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via

Keith Jun Hao Cheong1,2, Duen-Yi Huang1, Ponarulselvam Sekar2

  • 1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan.

Antioxidants (Basel, Switzerland)
|March 28, 2024
PubMed

Insights

Calcium/calmodulin-dependent serine protein kinase (CASK) silencing protects microglial cells from oxidative stress by inhibiting parthanatos. CASK inhibition of AKT and activation of AMPK pathways are key to this neuroprotective effect.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein vital for neuronal development and synaptic formation.
  • CASK has been previously linked to epidermal growth factor receptor (EGFR) in C. elegans vulval cell differentiation.

Purpose of the Study:

  • To investigate the role of CASK in CHME3 microglial cells, particularly in response to hydrogen peroxide (H2O2)-induced cell death.
  • To elucidate the molecular mechanisms underlying CASK's function in microglial cell survival and death pathways.

Main Methods:

  • CASK silencing was performed in CHME3 microglial cells.
  • Cells were treated with H2O2 to induce oxidative stress.
  • Key markers of cell death, mitochondrial function, reactive oxygen species (ROS) production, and signaling pathways (PARP-1, AKT, AMPK, EGFR) were analyzed.
  • Pharmacological inhibitors (olaparib) were used to probe specific pathways.

Main Results:

  • CASK silencing protected CHME3 cells from H2O2-induced death by reducing PARP-1 activation, mitochondrial dysfunction, and ROS production.
  • CASK silencing increased oxidative phosphorylation and AKT activation while decreasing AMPK activation, contributing to cell protection.
  • A non-canonical, AIF-independent parthanatos pathway was observed, distinct from the canonical pathway.
  • CASK silencing upregulated EGFR expression and phosphorylation, but EGFR activation was not protective.

Conclusions:

  • CASK plays a significant role in regulating microglial parthanatos induced by H2O2.
  • CASK influences parthanatos through modulation of PARP-1, AMPK, and AKT signaling pathways.
  • CASK emerges as a potential therapeutic target for central nervous system (CNS) disorders characterized by microglial cell death.
Keywords:
AKTAMPKCASKEGFRPARP-1hydrogen peroxidemicrogliamitochondrial dysfunctionparthanatos

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