Ferroptosis in ALS and Motor Neuron Disease: GPX4, Lipid Peroxidation, and Iron Chelation Therapies

What is the role of ferroptosis - an iron-dependent, lipid peroxidation-driven form of regulated cell death - in the pathogenesis of ALS and other motor neuron diseases? Specifically: (1) How does GPX4 (glutathione peroxidase 4) and its selenocysteine biochemistry confer vulnerability or resilience in motor neurons? (2) What is the mechanistic link between lipid peroxidation products (PEox, 4-HNE, MDA) and motor neuron death in SOD1, TDP-43, and FUS mutants? (3) Can iron chelation therapies (deferoxamine, deferiprone, clioquinol) slow disease progression via reduction of labile iron and reactive oxygen species? Generate specific, testable hypotheses grounded in published literature.

Resolution requires: (1) metabolomics/lipidomics of CSF and plasma from ALS patients (n≥100) vs healthy controls, identifying ≥3 ferroptosis markers (GPX4 activity, 4-HNE, F2-isoprostanes) that distinguish ALS from other motor neuron diseases; (2) post-mortem motor neuron iron staining (Perls’ stain) and GPX4 quantification showing regional vulnerability; (3) therapeutic trial of GPX4 activators or iron chelators showing slowed progression. Correlation without interventional validation is insufficient.