A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis

Area of Science:

• Biochemistry
• Neuroscience
• Cell Biology

Background:

• Ferroptosis is a regulated cell death pathway driven by lipid peroxidation.
• Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis, protecting cell membranes.
• The precise role of GPX4's membrane association in its protective function is not fully understood.

Purpose of the Study:

• To investigate the functional consequences of a GPX4 mutation (p.R152H) associated with early-onset neurodegeneration.
• To elucidate the role of GPX4 membrane anchoring in preventing ferroptosis and neurodegeneration.
• To explore ferroptosis as a therapeutic target for neurodegenerative diseases.

Main Methods:

• Structural and functional analyses of GPX4 variants.
• In vivo studies using spatiotemporal Gpx4 deletion or neuron-specific expression of GPX4^R152H in mice.
• Analysis of patient-derived induced pluripotent stem cell (iPSC)-cortical neurons and forebrain organoids.
• Neuroproteomic analysis.

Main Results:

• The GPX4 p.R152H mutation disrupts membrane anchoring but retains catalytic activity.
• GPX4 deficiency or expression of the R152H variant in neurons leads to cortical and cerebellar degeneration and neuroinflammation in mice.
• Patient-derived cells and organoids exhibit increased ferroptosis vulnerability and sensitivity to ferroptosis inhibitors.
• Affected brains show Alzheimer's-like molecular signatures.

Conclusions:

• Proper GPX4 membrane anchoring is essential for preventing ferroptosis and neurodegeneration.
• Ferroptosis is a significant driver of neurodegenerative pathology.
• Inhibition of ferroptosis presents a promising therapeutic avenue for neurodegenerative conditions.